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Journal of the Chilean Chemical Society
On-line version ISSN 0717-9707
J. Chil. Chem. Soc. vol.54 no.2 Concepción June 2009
http://dx.doi.org/10.4067/S0717-97072009000200018
J. Chil. Chem. Soc, 54, N° 2 (2009)
SYNTHESIS OF NOVEL TRYPTOPHAN DERIVATIVES OF POTENTIAL BIOLOGICAL ACTIVITY
RAFAT M. MOHAREB A,B* NADIA A. LOUCA C, GAMAL A. ELMEGEED C AND HANAA Y. HANA C
a Departament of Organic Chemistry, Faculty of Pharmacy, October University for Modem Sciences and Arts (MSA), El-Wahaat Road, October City, Egypt
bChemistry Department, Faculty of Science, Cairo University, Giza, Egypt
cHormone Department, National Research Centre, Dokki, Giza, Egypt
* e. mail: raafat_mohareb@yahoo. com
ABSTRACT
Tryptophan methyl ester 2 reacts with ethyl cyanoacetate to form acetomtrilocarbonyltryptophan methylester 3. The latter reacts with cyanomethylene reagents, hydrazines, cyanomethylenes and sulfur to form the corresponding a-pyrido-3-indolopropanoate derivatives 6a,b, pyrazolyltryptophan methyl ester derivatives 8a,b and thiophenotryptophan methyl ester derivatives 10a,b, respectively. Also compound 3 reacts with benzaldehyde to give the condensated product 12. The reactivity of the latter product towards chemical reagents was studied to form pyridine, pyrazole and isoxazole derivatives.
Keywords: Teyptophane, pyrazd, pyridine, 1,3- oxazine.
INTRODUCTION
The development of potential therapeutic agents based on the structure of peptides has stimulated an interest in the design and synthesis of unnatural amino acids [1-3]. Thus, numerous chemical transformations of amino acids have been reported [4]. índole and it's derivatives have been a topic of research interest for over a century [5,6]. This, is in part, due to the fact that Índole moieties are found in a variety of naturally occurring compounds that exhibit various physiological properties [7,8]. Tryptophan is one of the most important amino acids which containing Índole moiety. However, to our knowledge, few investigations have been reported concerning its uses in the formation of cyclic tryptophan derivatives [9-12]. The reaction of tryptophan with cyanoacetates is known to produce cyanoamides in the aim of forming photo-active cross-linking bioprobes [13,14]. In view of these observations and in continuation with studies involving the synthesis of unusual hormones and amino acids derivatives [15-17], we have used in this study, L-tryptophan is used to form new heterocyclic compounds of potential biological activities.
RESULTS AND DISCUSSION
The reaction of tryptophan (1) with methanol in acetyl chloride solution afforded the corresponding tryptophan methyl ester 2 (Scheme 1). Compound 2 reacted with an equimolar amount of ethyl cyanoacetate in 1,4-dioxan under reflux to give the methyl a-imino(acetonitrilocarbamido)-3-indolopropanoate (3) via elimination of ethanol. The mass spectrum of compound 3 showed molecular ion peak at m/z 286 (25%). The IR spectrum of compound 3 revealed the presence of NH stretching at v 3400-3360 cm-1, one CN group stretching at v 2220 cm-1 and two C=0 groups stretching at v 1730 and 1680 cm-1. Also the [H NMR spectrum of compound 3 showed two D20-exchangeable singlets at 8 8.65 and 8.76 for the two NH groups (cf experimental section). Moreover, the 13C NMR spectrum showed 8 22.6 (CH3), 28.9, 44.2 (2 CH2), 50.2 (CH), 115.1, 116.7, 118.4, 120.4, 121.4, 122.6, 142.6 (pyrole, benzene C), 172.6, 174.8 (2 C=0).
To improve the pharmaceutical properties of the tryptophan molecule, we have outlined the synthesis of several Índole derivatives containing heterocyclic moiety. Therapeutic agents containing pyridine, thiophene, and pyrazole moieties have attracted the attention of researchers in pharmaceutical chemistry; these heterocycles have been found to show various biological activities [18,19]. Compound 3 seemed to be an interest candidate for further chemical transformations to form Índole derivatives with potential biological activity. The reactivity of compound 3 towards the reaction with active methylene reagents was investigated. Thus, compound 3 reacted with equimolar amount of either malononitrile (4a) or ethyl cyanoacetate (4b) in ethanolic triethylamine solution gave the a-pyrido-3-indolopropanoate derivatives 6a,b, respectively. Formation of the latter products took place via the intermediate formation of 5a,b which underwent ready intramolecular cyclization to give compounds 6a,b (Scheme 2). The IR spectrum of each of 6a and 6b showed two CN groups stretching at v 2200 and 2225 cm-1, respectively. The :H NMR of compound 6a showed a singlet at 8 4.62 (4H, D20-exchangeable) for the two NH2 groups while that of compound 6b showed a singlet at 8 4.41 (2H, D20-exchangeable) for one NH2 group and a singlet at 8 10.05 for the OH group. Moreover, each of compounds 6a,b showed a singlet at 8 6.23 and 6.34, respectively for the pyridine ring proton at C-3 (cf. experimental section).
The study also extended to the reactivity of compound 3 towards nitrogen nucleophilic reagents. Thus, compound 3 reacted with equimolar amounts of either hydrazine hydrate or phenylhydrazine in refluxing ethanol containing a catalytic amount of triethylamine to give the corresponding pyrazolyltryptophan methyl ester derivatives 8a,b. The reaction took place via a simple addition of hydrazine hydrate or phenylhydrazine to the CN group in compound 3 to give the intermediates 7a,b which readily afforded compounds 8a,b via water elimination (Scheme 2). Moreover, compound 3 reacted with hydrox-ylamine hydrochloride in cold ethanolic sodium acetate solution to give the corresponding oxadiazinomethylenoindole derivative 9 (Scheme 2). Structures of compounds 8a,b and 9 were supported by their compatible analytical and spectral data (cf. experimental section).
Compound 3 reacted with equimolar amounts of either malononitrile 4a or ethyl cyanoacetate 4b and elemental sulfur in ethanolic triethylamine solution under reflux to afford the corresponding thiophenotryptophan methyl ester derivatives 10a,b (Scheme 3). The IR spectrum of compound 10a revealed the presence of two CN groups stretching at v 2210 and 2225 cm-1 and the 'HNMR spectrum revealed the presence of D20-exchangeable singlet (2H) at δ 5 4.58 for the NH2 group and two D20-exchangeable singlets at 8 10.78 (1H) and 5 11.94 (1H) for the two NH groups. On the other hand, the IR spectrum of 10b showed the presence of one CN group stretching at v 2200 cm-1 and its 1H NMR spectrum showed a triplet at δδ 8 1.23 beside a quartet at δ 8 4.24 due to the ethyl ester group, in addition to the NH2 and the two NH singlet signals at δ 8 6.50, 10.71 and 10.88, respectively. The cyanomethylene moiety of compound 3 coupled easily with benzenediazonium chloride in cold ethanolic sodium acetate solution to give the phenylhydrazo derivative 11 based on 1H NMR spectrum which showed, beside the expected chemical shifts, three NH singlets at δ 9.25 and 9.97-9.99 (D O-exchangeable) (Scheme 3).
The reaction of compound 3 with equimolar amount of benzaldehyde in ethanolic triethylamine solution under reflux afforded the condensated product benzalacetonitrilocarbonyltryptophan methyl ester derivative 12 (Scheme 4). The reactivity of the α,β -unsaturated nitrile moiety of compound 12 towards the reaction with various chemical reagents was investigated. Thus, 12 reacted with either malononitrile 4a or ethyl cyanoacetate 4b in refluxing ethanolic triethylamine solution to give the methyl a-pyrido-1-yl-3-indolopropanoate derivatives 14a,b, respectively via the intermediacy of 13a,b (Scheme 4). The IR spectrum of compound 14a revealed the presence of two CN groups at v 2220 and 2215 cm-1 and the -1H NMR spectrum of compound 14a showed two D20-exchangeable singlets at δ 8 4.46 (2H) and δ 11.02 (1H) corresponding to the NH2 and NH groups, respectively. The mass spectrum of compound 14b showed a molecular ion peak at m/z 486 (35%) and the :H NMR spectrum of 14b revealed a triplet at δ1.33 and a quartet at 8 4.32 which is characteristic to ethyl ester group (cf. experimental section).
The reactivity of compound 12 towards the reaction with nucleophilic reagents was investigated. Thus, the reaction of 12 with equimolar amounts of either hydrazine hydrate or phenylhydrazine in ethanolic triethylamine solution under reflux afforded the corresponding carbonylpyrazolotryptophan methyl ester derivatives 15a,b, respectively (Scheme 5). Similarly compound 12 reacted with hydroxylamine hydrochloride in ethanol containing sodium acetate solution to afford the isooxazolotryptophan methyl ester derivative 16 (Scheme 5). The chemical structures of compounds 15a,b and 16 were confirmed via the analytical and spectral data (cf. experimental section).
Tryptophan (1) reacted with an equimolar amount of ethyl cyanoacetate in refluxing dimethylformamide solution to give the acetonitrilocarbonyl tryptophan 17 (Scheme 5). The IR spectrum of compound 17 revealed the presence of two NH groups stretching at v 3430-3385 cm-1, and one CN group stretching at v 2220 cm-1 in addition to two C=0 groups stretching at v 1705 and 1680 cm-1. Also the 1H NMR spectrum of compound 17 showed two singlets at δ 8.75 and 8.82 (D20-exchangeable) for the two NH groups and a singlet at δ 11.15 for the OH group (cf. experimental section). Compound 17 reacted with an equimolar amount of benzaldehyde in ethanol/piperidine solution under reflux to afford the condensed product benzaloacetonitrilocarbonyl-tryptophan 18 (Scheme 5). Moreover, compound 17 easily coupled with benzenediazonium chloride in cold ethanolic sodium acetate solution to afford the phenylhydrazo derivative 19 (Scheme 5), based on -1H NMR spectrum which showed, beside the expected chemical shifts, three NH singlets at δ 8.51 and 9.32-9.36 (D20-exchangeable). The structures of the latter products 18 and 19 were confirmed based on their compatible elemental and spectral analyses (cf. experimental section).
EXPERIMENTAL SECTION
The starting pure powder of L-tryptophan was purchased from Sigma Company, USA. The appropriate precautions in handling moisture sensitive compounds were undertaken. All melting points of the newly synthesized compounds were measured using an electrothermal capillary melting point apparatus and are uncorrected. The IR spectra are expressed in cm"1 and recorded in KBr pellets on a Pa-9721 IR spectrometer (Shimadzu, Japan). :H- and 13C NMR spectra were obtained on a Varían EM-390 90 MHz spectrometer in DMSO-d6 as solvent, using TMS as internal reference and chemical shifts (8) are expressed in ppm. Mass spectra were recorded on a GCMS-QP 1000 Ex spectra mass spectrometer operating at 70 eV Equipment (Germany). Elemental analyses were preformed with all final compounds by Microanalytical Data Unit at The National Research Centre, Giza, Egypt. The reactions were followed using TLC analyses which were performed using Merck 60 F254 aluminum sheets and visualized by UV light (254 run). Although tryptophan methyl ester is commercially available in the hydrochloride form we preferred to syntheses the native methyl ester via the procedure indicated below.
Methyl «-amino-3-indolopropanoate (2). To a solution of tryptophan 1 (10.2 g, 0.05 mol) in methanol (5 niL) equivalent amount of acetylchloride (3.77 mL, 0.05 mol) in methanol (30 mL) was added drop wise with stirring at 0°C. The reaction mixture was stirred for 24 h, and then evaporated under vacuum. The formed solid product neutralized by sodium carbonate solution (1 N), extracted by chloroform and dried by anhydrous sodium sulfate. The solid product formed after evaporation of the solvent, filtered off, dried and crystallized from methanol. White crystals, yield 55% (6.0 g), mp 152-153°C IR (v/ cm1): 3450-3235 (NH2,NH), 3050 (CH-aromatic) 2985, 2865 (CH3, CH2) 1730 (C=0), 1620 (C=C). -1H NMR (δ ppm): 3.35 (s, 3H, CH3), 3.43 (m, 2H, CH2), 3.75 (m, 1H, CH), 6.57 (s, 2H, NH2, D20-exchangeable), 6.64 (s, 1H, CH), 7.51 (m, 4H, C6H4), 8.92 (s, 1H, NH, unexchangeable). MS (m/z, %): 218 (M+', 45%). Anal. Caled, for C12H14N202 (218.26): C, 66.03; H, 6.46; N, 12.83. Found: C, 65.79; H, 6.25; N, 12.52.
Methyl «-imino(acetonitrilocarbamido)-3-indolopropanoate (3). To a solution of 2 (1.09 g, 0.005 mol) in 1,4-dioxan (30 mL), equivalent amount of ethyl cyanoacetate 4b (0.56 g, 0.005 mol) was added. The reaction mixture was heated under reflux for 3h. The solid product formed by evaporation under vacuum was filtered off, dried and crystallized. White crystals from diox-ane, yield 75% (1.07 g), mp 128-130°C IR (v/cm-1): 3400-3360 (2NH), 3050 (CH-aromatic), 2985, 2659 (CH3, CH2), 2220 (CN), 1730, 1680 (2C=0), 1620 (C=C). -1H NMR (δ ppm): 3.38 (s, 3H, CH3), 3.45 (m, 2H, CH2), 3.48 (s, 2H, CH2CN), 3.78 (m, 1H, CH), 6.95 (s, 1H, CH), 7.01-7.49 (m, 4H, C6H4), 8.65, 8.76 (2s, 2H, 2NH, D20-exchangeable). 13C NMR (S): 22.6 (CH3), 28.9, 44.2 (2 CH2), 50.2 (CH), 115.1, 116.7, 118.4, 120.4, 121.4, 122.6, 142.6 (pyrole, benzene C), 172.6, 174.8 (2 C=0). MS (m/z, %): 286 (M++1), 25%), 260 (M+'-CN, 25%), 203 (M+'-NHCOCH2CN, 23%), 130 (indolomethylene fragment, C9H8N, 100%). Anal. Caled, for C15H15N303 (285.30): C, 63.15; H, 5.30; N, 14.73. Found: C, 63.42; H, 5.37; N, 14.39.
Methyl α-(2,4-diamino-5-cyano-6-oxopyrido-l-yl)-3-indolopropanoate (6a), Methyl α-(4-Amino-5-cyano-2-hydroxy-6-oxopyido-l-yl) -3-indolo-propanoate (6b)
General Procedure
To a solution of Compound 3 (1.42 g, 0.005 mol) in ethanol (30 mL), containing a catalytic amount of triethylamine (1 mL, 0.01 mol), equivalent amount of either malononitrile 4a (0.33 g, 0.005 mol) or ethyl cyanoacetate 4b (0.56 g, 0.005 mol) was added. The reaction mixture in each case was heated under reflux for 3h and then was cooled at room temperature, poured over ice/ water mixture and neutralized with dilute hydrochloric acid. The formed solid product, in each case filtered off, dried and crystallized from the appropriate solvent.
Compound 6a: Yellow crystals, from MeOH, yield 77% (1.35g), mp 150-152°C. IR (v/cm-1): 3450-3250 (2NH2, NH), 2980, 2865 (CH3, CH2), 2200 (CN), 1730, 1690 (2C=0). -1H NMR (δ ppm): 3.33 (s, 3H, CH3), 3.43 (m, 2H, CH2), 3.70 (m, 1H, CH), 4.62 (s, 4H, 2NH2, unexchangeable), 6.23 (s, 1H, C3-pyridine ring proton), 6.62 (s, 1H, CH), 7.00-7.32 (m, 4H, C6H4), 10.87 (s, 1H, NH, unexchangeable). MS (m/z, %): 351 (M+', 55%), 325 (M+'-CN, 35%), 130 (indolomethylene fragment, C9H8N, 100%). Anal. Caled, for C18H17N503 (351.36): C, 61.53; H, 4.87; N, 19.93. Found: C, 61.21; H, 4.73; N, 19.67.
Compound 6b: Pale yellow crystals, from MeOH, yield 82% (1.44 g), mp 198-199°C IR (v/cm1): 3450-3250 (NH2, NH), 3050 (CH-aromatic), 2225 (CN), 1730, 1700 (2C=0), 1630 (C=C). 1H NMR (δ ppm): 3.38 (s, 3H, CH3), 3.43 (m, 2H, CH2), 3.75 (m, 1H, CH), 4.41 (s, 2H, NH2, D20-exchangeable), 6.34 (s, 1H, C3-pyridine ring proton), 6.82 (s, 1H, CH), 7.11-7.54 (m, 4H, C6H4), 10.05 (s, 1H, OH). Anal. Caled, for C18H16N404 (352.35): C, 61.35; H, 4.57; N, 15.90. Found: C, 61.19; H, 4.28; N, 15.73.
Methyl α-imino(5-aminopyrazolo-3-yl)-3-indolopropanoate (8a)
Methyla-imino(5-amino-2-phenylpyrazolo-3-yl)-3-indolopropanoate (8b)
General Procedure. To a solution, of compound 3 (1.42 g, 0.005 mol) in ethanol (30 mL), containing a catalytic amount of triethylamine (2 mL, 0.02 mol), equivalent amount of either hydrazine hydrate (0.25 g, 0.005 mol) or phenylhydrazine (0.54 g, 0.005 mol) was added. The reaction mixture in each case was heated under reflux for 5 h and then was cooled at room temperature, poured over ice/water mixture and neutralized with dilute hydrochloric acid.
The formed solid product, in each case, was filtered off, washed with water and crystallized from the appropriate solvent.
Compound 8a: White crystals, from EtOH, yield 72% (1.08 g), mp 154-155°C. IR (v/cnv1): 3450-3250 (NH2, 3NH), 3050 (CH-aromatic), 2985, 2865 (CH3, CH2), 1720 (C=0), 1660 (C=N), 1620 (C=C). 'H NMR (8 ppm): 3.35 (s, 3H, CH3), 3.46 (m, 2H, CH2), 3.73 (m, 1H, CH), 4.50 (s, 2H, NH2, Dp-exchangeable), 5.83 (s, 1H, CH pyrazole), 6.51 (s, 1H, CH), 6.98-7.40 (m, 4H, C6H4), 9.83, 10.80, 10.92 (3s, 3H, 3NH, D20-exchangeable). Anal. Calcd. for C15H17N502 (299.33): C, 60.18, H, 5.72, N, 23.39. Found: C, 59.90; H, 5.43; N, 23.64.
Compound 8b: Brown crystals, from EtOH, yield 75% (1.40 g), mp. 90-91°C. IR (v/cm1): 3400-3250 (NH2, 2NH), 3050 (CH-aromatic), 2985, 2865 (CH3, CH2), 1730 (C=0), 1660 (C=N), 1620 (C=C). 'H NMR (δ ppm): 3.40 (s, 3H, CH3), 3.51 (m, 2H, CH2), 3.74 (m, 1H, CH), 4.23 (s, 2H, NH2, Dp-exchangeable), 5.83 (s, 1H, CH pyrazole), 6.33 (s, 1H, CH), 7.32-7.55 (m, 9H, C6H4, C6H5), 10.80, 10.92 (2s, 2H, 2NH, D20-exchangeable). MS (m/z, %): 374 (M+'-l; 34%), 298 (M+'- C6H5, 57%), 77 (C6H5; 70%). Anal. Calcd. for C21H21N5O2 (375.43): C, 67.18; H, 5.62; N, 18.65. Found: C, 67.17; H, 5.49; N, 18.52.
3-Acetonitrilo-6-hydroxy-3-methylenoindolo-2,l54 oxadiazine (9). To a solution of compound 3 (1.42 g, 0.005 mol) in ethanol (30 mL), containing a catalytic amount of sodium acetate (1.0 g) equivalent amount of hydroxy-lamine hydrochloric acid (0.35 g, 0.005 mol) in H20 (5 mL) was added with stirring. The reaction mixture was stirred with warming for 30min, left to cool to 20 °C. The formed solid product was triturated ice/water mixture, collected by filtration and crystallized from MeOH. White crystals, yield 73% (0.97 g), mp 94-95°C. IR (v/cm1): 3300-3200 (2NH, OH), 3050 (CH-aromatic), 2985, 2865 (CH3, CH2), 2200 (CN), 1660 (C = N), 1620 (C = C). 'H NMR (δ ppm): 1.25 (s, 2H, CH2), 3.91 (s, 2H, CH2), 6.64 (s, 1H, CH), 7.00-7.71 (m, 4H, C6H4), 9.22, 9.52 (2s, 2H, 2NH, D20-exchangeable), 10.89 (s, 1H, OH). 13C NMR (d): 20.3, 21.6 (2CH2), 88.4 (oxadiazine C-4), 118.7, 119.4, 120.6, 120.9, 121.5, 130.4, 136.9 (benzene, pyrrole C), 118.7 (CN). 179.8 (oxadiazine C-3). Anal. Calcd. for C14H12N402 (268.28). C, 62.68; H, 4.50; N, 20.83. Found: C, 62.59; H, 4.53; N, 20.77.
Methyl α-N-(5-amino-2,4-dicyanothiopheno-3-yl)-3-indolopropanoate (10a)
Methyl α-N-(ethyl 5-amino-2-cyanothiopheno-3-yl-4-carboxylate)-3-indolo-propanoate (10b)
General Procedure
To a mixture of compound 3 (1.42 g, 0.005 mol), elemental sulfur (0.16 g, 0.005mol) and either malononitrile 4a (0.33 g, 0.005 mol) or ethyl cyanoac-etate 4b (0.56 g, 0.005 mol) in ethanol (30 mL), triethylamine (0.5 mL, 0.005 mol) was added. The reaction mixture in each case was heated under reflux for 4 h and then was cooled at room temperature, poured over ice/water mixture and neutralized with dilute hydrochloric acid. The formed solid product was filtered off, dried and crystallized from the appropriate solvent.
Compound 10a: Brown crystals, from MeOH, yield 73% (1.33 g), mp 106-107°C. IR (v/cm1): 3400-3250 (NH2, 2NH), 3050 (CH-aromatic), 2965, 2865 (CH3, CH2), 2210, 2225 (2CN), 1730 (C = O), 1620 (C = C). 1H NMR (δ ppm): 3.39 (s, 3H, CH3), 3.53 (m, 2H, CH2), 3.75 (m, 1H, CH), 4.58 (s, 2H, NH2, Dp-exchangeable), 6.53 (s, 1H, CH), 7.01-7.60 (m, 4H, C6H4) 10.78, 11.94 (2s, 2H, 2NH,D20-exchangeable). anal. Calcd. for C18H15N5S02 (365.42): C, 59.16; H, 4.13; N, 19.16; S, 8.77. Found: C, 58.91; H, 4.05; N, 19.02; S, 8.51.
Compound 10b: Pale brown crystals, from EtOH, yield 75% (1.54g), mp 91-92°C. IR (v/cm1): 3400-3250 (NH2, 2NH) 3050 (CH-aromatic), 2965, 2865 (CH3, CH2), 2200 (CN), 1730, 1700 (2C=0), 1620 (C=C). 1H NMR (δ ppm): 1.23 (t, 3H, J = 6.8 Hz, ester CH3), 3.41 (s, 3H, CH3), 3.53 (m, 2H, CH2), 3.75 (m, 1H, CH), 4.24 (q, 2H, J = 6.8 Hz, ester CH2), 6.50 (s, 2H, NH2, Dp-exchangeable), 6.99 (s, 1H, CH), 7.04-7.49 (m, 4H, C6H4), 10.71, 10.88 (2s, 2H, 2NH, Dp-exchangeable). MS (m/z, %): 412 (M+', 62%). Anal. Calcd. for C20H20N4O4S (412.47): C, 58.23; H, 4.88; N, 13.58; S, 7.77. Found: C, 58.11; H, 4.72; N, 13.43; S, 7.62.
Methyl α-N-(phenylhydrazoacetonltrilocarbamido)-3 indolopropano-ate (11). A solution of compound 3 (1.42 g, 0.05 mol), in ethanol (30 mL) containing a catalytic amount of sodium acetate (1.0 g) was cooled to 0-5°C and then treated gradually with a cold solution of benzenediazonium chloride (prepared from the appropriate quantities of aniline, HC1 and NaN02). After addition of the diazonium salt was completed, the reaction mixture was stirred at room temperature for 30 min. The solid product, separated upon dilution with cold water, was filtered off, washed with water several times, dried and crystallized from EtOH to yield 72% (1.40 g) pale brown crystals, mp 94-95°C. IR (v/cm1): 3400, 3300 (3NH), 3050 (CH-aromatic), 2985, 2865 (CH3, CH2), 2200 (CN), 1720, 1690 (2C=0), 1660 (C=N), 1630 (C=C). :H NMR (8 ppm): 1.27 (s, 1H, CH), 3.37 (s, 3H, CH3), 3.47 (m, 2H, CH2), 3.70 (m, 1H, CH), 5.64 (s, 1H, CH), 7.67-7.74 (m, 9H, C6H4, C6H5), 9.25, 9.97-9.99 (3s, 3H, 3NH, Dp-exchangeable). Anal. Calcd. for C21H19Np3 (389.41): C, 64.77; H, 4.91; N, 17.98. Found: C, 64.67; H, 4.89; N, 17.88.
Methyl α-N-(benzaloacetonitrilocarbamido)-3-indolopropanoate (12). To a solution of compound 3 (1.42 g, 0.005 mol) in ethanol (30 mL), containing triethylamine (1 mL, 0.01 mol), equivalent amount of benzaldehyde (0.53 g, 0.005 mol) was added. The reaction mixture was heated under reflux for 3h. Then poured over ice/water mixture and neutralized with dilute hydrochloric acid. The formed solid product filtered off, dried and crystallized from EtOH. Pale brown crystals, yield 77% (1.43 g), mp 81-82°C. IR (v/cm1): 3400-3200 (2NH), 3050 (CH-aromatic), 2985, 2865 (CH3, CH2), 2200 (CN), 1720, 1690 (2C=0). 1H NMR (8 ppm): 3.40 (s, 3H, CH3), 3.59 (m, 2H, CH2), 3.72 (m, 1H, CH), 4.10 (s, 1H, CH), 7.08 (s, 1H, CH), 7.31-7.72 (m, 9 H, C6H4, C6H5), 8.42, 10.93 (2s, 2H, 2NH, D20-exchangeable). MS (m/z, %): 374 (M+', 22%), 315 (M+'-COOCH3, 21%), 284 (M+'- CHPh, 20%), 130, (indolomethylene fragment, C9H8N, 100%). Anal. Calcd. for C22H19N303 (373.41): C, 70.76; H, 5.12; N, 11.25. Found: C, 70.55; H, 5.11; N, 11.13.
Methyl α-(6-amino-3,5-dicyano-2-oxo-4-phenylpyrido-1-yl) -3-indolo-propanoate (14a)
Methyl α-(ethyl 6-amino-3-cyano-2-oxo-4-phenylpyrido-1-yl-5-carboxylate)-3-indolopropanoate (14b)
General Procedure. To a solution of compound 12 (1.86 g, 0.005 mol) in ethanol (30 mL), containing (1 mL, 0.01 mol), equivalent amount of either malononitrile 4a (0.33 g, 0.005 mol), or ethyl canoacetate 4b (0.56 g, 0.005 mol) was added. The reaction mixture, in each case, was heated under reflux for 3h then poured over ice/water mixture and neutralized with hydrochloric acid. The formed solid product, in each case filtered off, dried, and crystallized from the appropriate solvent.
Compound 14a: yellow crystals, from EtOH, yield 72% (1.58g), mp 118-120°C. IR (v/cnv1): 3450-3350 (NH2), 3300, 3200 (2NH), 3050 (CH-aromatic), 2985, 2865 (CH3, CH2), 2220, 2215 (2 CN), 1730, 1690 (2C = O). :H NMR (8 ppm): 3.39 (s, 3H, CH3), 3.53 (m, 2H, CH2), 3.75 (m, 1H, CH), 4.46 (s, 2H, NH2, Dp-exchangeable), 6.51, 6.57 (2d, 2H, J = 9.7 Hz, 2CH), 6.60 (s, 1H, CH), 7.02-7.60 (m, 9 H, C6H5, C6H4), 11.02 (s, 1H, NH, D20-exchangeable). 13C NMR (8): 18.9 (CH2), 48.7 (CH3), 55.8 (CH), 80.9, 11.6, 113.4, 115.9, 118.4, 120.1, 122.7, 130.5, 133.8 (benzene, pyrrole C), 118.6, 119.2 (2 CN), 160.3, 170.4 (2CO). Anal. Calcd. for C2JH21Np3 (439.37): C, 68.32; H, 4.81; N, 15.93. Found: C, 68.25; H, 4.73; N, 15.85.
Compound 14b: White crystals, from dioxane, yield 77% (1.87 g), mp 77-78°C. IR (v/cm"1): 3450-3250 (NH2, NH), 3050 (CH-aromatic), 2985, 2865 (CH3, CH2), 2200, (CN), 1735, 1730, 1700 (3C=0), 1630 (C=C). 1H NMR (δ ppm): 1.33 (t, J= 6.8 Hz, 3H, ester CH3), 3.45 (s, 3H, CH3), 3.52 (m, 2H, CH2), 3.68 (m, 1H, CH), 4.32 (q, 2H, J = 6.8 Hz, ester CH2), 5.18 (s, 2H, NH2, Dp-exchangeable), 6.46, 6.52 (2d, 2H, J = 9.7 Hz, 2CH), 6.73 (s, 1H, CH), 7.23-7.92 (m, 9H, C6H5, C6H4), 10.93 (s, 1H, NH, D20-exchangeable). MS (m/z, %): 486 (M+', 35%), 202 [M+'-C15H14Np3 (substituted pyridine fragment), 34%], 130 (indolomethylene fragment, C9H8N, 100%). Anal. Calcd. for C27H26Np, (486.53): C, 66.65; H, 5.38; N, 11.51. Found: C, 66.75; H, 5.28; N, 11.31.
Methyl-α-iminocarbonyl(3-amino-5-phenylpyrazolo-4-yl) -3-indolo-propanoate (15a)
Methyl α-iminocarbonyl(3-amino-l,5-diphenylpyrazolo-4-yl) -3-in-dolopropanoate (15b)
General Procedure
To a solution of compound 12 (1.86 g, 0.005 mol) in ethanol (30 mL), containing triethylamine (1 mL, 0.01 mol), either hydrazine hydrate (0.25 g, 0.005 mol) or phenylhydrazine (0.54 g, 0.005 mol) was added. The reaction mixture, in each case, was heated under reflux for 4h then poured over ice/ water mixture and neutralized with hydrochloric acid. The formed solid product, in each case, was filtered off, washed with water and crystallized from the appropriate solvent.
Compound 15a: Yellow crystals, from EtOH, yield 77% (1.55 g), mp 100-101°C. IR (v/cnv1): 3450-3150 (NH2, 3NH), 3050 (CH-aromatic), 2985, 2865 (CH3, CH2), 1730, 1700 (2C=0), 1660 (C=N), 1630 (C=C). 1H NMR (δ ppm): 3.43 (s, 3H, CH3), 3.56 (m, 2H, CH2), 3.75 (m, 1H, CH), 4.83 (s, 2H, NH2, unexchangeable), 6.93 (s, 1H, CH), 7.05-7.72 (m, 9 H, C6H5, C6H4), 9.48, 10.91, 10.92 (3s, 3H, 3NH, D20-exchangeable). MS (m/z, %): 404 (M+'+l; 70%), 336 (M+'- C6H5, 50%), 77 (C6H5; 36%). Anal. Caled, for C22H21N503 (403.44): C, 65.49; H, 5.24; N, 17.35. Found: C, 65.32; H, 5.11; N, 17.15.
Compound 15b: White crystals from MeOH, yield 72% (1.72 g), mp 136-137°C. IR (v/cm1): 3450-3250 (NH2, 2NH), 3050 (CH-aromatic), 2985, 2685 (CH3, CH2), 1730, 1690 (2C=0), 1660 (C=N), 1630 (C=C). 1H NMR (5 ppm): 3.43 (s, 3H, CH3), 3.53 (m, 2H, CH2), 3.75 (m, 1H, CH), 4.85 (s, 2H, NH2, D20-exchangeable), 6.73 (s, 1H, CH), 6.76-7.80 (m, 14H, 2C6H5, C6H4), 10.37, 10.93, (2s, 2H, 2NH, D20-exchangeable). Anal. Caled, for C28H2JN503 (479.54): C, 70.13; H, 5.25; N, 14.60. Found: C, 69.99; H, 5.11; N, 14.42.
Methyl a-iminocarbonyl(3-amino-5-phenyllsooxazolo-4-yl) -3-indolo-propanoate (16). To a solution of compound 12 (1.86 g, 0.005 mol) in ethanol (30 mL), containing a catalytic amount of sodium acetate (1.0 g), equivalent amount of hydroxylamine hydrochloride acid (0.35 g, 0.005 mol) in ethanol (10 mL) was added with stirring and warming. The solid product formed at room temperature triturated with ice/water mixture and collected by filtration. Yellowish crystals, from MeOH, yield 75% (1.51 g), mp 136-137°C. IR (v/ cm1): 3450-3250 (NH2, 2NH), 3050 (CH-aromatic), 2985, 2865 (CH3, CH2), 1730, 1690 (2C=0), 1660 (C=N), 1630 (C=C). 1H NMR (δ ppm): 3.38 (s, 3H, CH3), 3.55 (m, 2H, CH2), 3.72 (m, 1H, CH), 4.83 (s, 2H, NH2, D20-exchange-able), 6.31 (s, 1H, CH), 7.04-7.71 (m, 9 H, C6H4, C6H5), 10.91, 10.97 (2s, 2H, 2NH, D20-exchangeable). Anal. Caled, for C22H20N4O4 (404.43): C, 65.33; H, 4.98; N, 13.85. Found: C, 65.11; H, 4.72; N, 13.79.
α-Imino(acetoiiitrilocarbamido)-3-indolopropionic acid (17). To a solution of tryptophan 1 (1.02 g, 0.005 mol) in dimethyl formamide (30 mL), equimolar amount of ethyl cyanoacetate 4b (0.56 g, 0.005 mol) was added. The reaction mixture was heated under reflux for 4h and then was evaporated in vacuum. The remaining product was triturated with diethyl ether, and the solid product was collected by filtration. Yellow crystals, from EtOH, yield 79% (1.07 g), mp 146-147°C. IR (v/cm1): 3430-3385 (2NH), 3050 (CH-aromatic), 2680 (CH2), 2220 (CN), 1705, 1680 (2C=0), 1620 (C=C). 'H NMR (δ ppm): 3.43 (m, 2H, CH2), 3.49 (s, 2H, CH2CN), 3.75 (m, 1H, CH), 6.95 (s, 1H, CH), 7.01-7.49 (m, 4H, C6H4), 8.75, 8.82 (2s, 2H, 2NH, D20-exchangeable), 11.15 (s, 1H, OU).Anal. Caled, forC14H13N303 (271.28): C, 61.98; H, 4.83; N, 15.48. Found: C, 61.77; H, 4.65; N, 15.21.
α-Imino(benzaloacetonitriocarbamido)-3-indolopropionic acid (18).
To a solution of compound 17 (1.35 g, 0.005 mol), in ethanol (30 mL), containing piperidine (0.85 mL, 0.01 mol), equivalent amount of benzaldehyde (0.53 g, 0.005 mol) was added. The reaction mixture was heated under reflux for 3h then poured over ice/water mixture and neutralized with dilute hydrochloric acid. The formed solid product filtered off, dried and crystallized from dilute ethanol. Pale brown crystals, yield 75% (1.21 g), mp 177-178°C. IR (y/cm1): 3400-3200 (2NH), 3050 (CH-aromatic), 2865 (CH2), 2200 (CN), 1720, 1690 (2C=0). 'H NMR (δ ppm): 3.53 (m, 2H, CH2), 3.72 (m, 1H, CH), 4.10 (s, 1H, CH), 6.48 (s, 1H, CH), 7.31-7.72 (m, 9H, C6H4, C6H5), 8.42, 9.11 (2s, 2H, 2NH, D20-exchangeable), 11.15 (s, 1H, OH). MS (m/z, %): 359 (M+, 35%). Anal. Caled, for C21H17N303 (359.38): C, 70.18; H, 4.76; N, 11.69. Found: C, 70.31; H, 4.53; N, 11.45.
α-Imino(phenylhydrazoacetonitrilocarbamido)-3-indolopropionic acid (19). A solution of compound 17 (1.35 g, 0.005 mol), in ethanol (30 mL), containing a catalytic amount of sodium acetate (1.0 g) was cooled to 0-5°C and then gradually with a cold solution of benzenediazonium chloride [prepared by adding sodium nitrite solution (0.7 g, 0.01 mol) to a cold solution of aniline 0.45 g, 0.005 mol) with continuous stirring]. After addition of diazo-nium salt was completed, the reaction mixture was stirred at room temperature for 30 min. The solid product, separated upon dilution with cold water, was filtered off, washed with water several times, dried and crystallized. Brown crystals from EtOH, yield 75% (1.40 g), mp 79-80°C. IR (y/cm1): 3430-3335 (3NH), 3050 (CH-aromatic), 2865 (CH2), 2200 (CN), 1720, 1690 (2C=0), 1660 (C=N), 1630 (C=C). 'H NMR (δ ppm): 1.27 (s, 1H, CH), 3.28 (m, 2H, CH2), 3.75 (m, 1H, CH), 5.64 (s, 1H, CH), 7.67-7.74 (m, 9H, C6H4, C6H5), 8.51, 9.32-9.36 (3s, 3H, 3NH, unexchangeable), 11.40 (s, 1H, OH). 13C NMR (8): 25.0 (CH2), 55.8 (CH), 80.7, 111.6, 113.6, 114.8, 118.6, 120.4, 122.2, 130.4, 133.9 (benzene, pyrrole C), 117.6 (CN), 150.3, 166.4 (2 CO), 177.9 (C=N). Anal. Caled, for C20H17N5O3 (375.39): C, 63.99; H, 4.56; N, 18.65. Found: C, 63.78; H, 4.43; N, 18.59.
ACKNOWLEDGEMENT
Mohareb R. M. expressed his deepest thank to the Alexander von Hum-boldt Foundation for financing support during his stay in Germany, Stuttgart University and completing this work.
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(Received: May 27, 2008 -Accepted: December 12, 2008)
