, Hydrochloride salt 11e was prepared from 10e in 86% yield as tannish yellow powder, Mp >, vol.250

2. and H. , 03 (s, 2H, OCH 2 O), vol.4

, C-4', Ar), ES + HRMS, m/z: 209.1292 found, vol.147

2. and H. , 85 (s, 3H, OCH 3 ); 4.21 (s, 2H, H-4), Ar), vol.3, issue.2

H. Nmr-;-m, 2. , and H. , 77 (s, 3H, OCH 3 ); 4.08 (t, 2H, J = 5.5 Hz, H-4), vol.3, p.43

, C-4', Ar); 115.7 (C-2', Ar), vol.114

, ES + HRMS, m/z: 195.1497 found

, 5-Dimethoxybenzylamino)propylamine hydrochloride (11h)

, Hydrochloride salt 11h was prepared from 10h in 98% yield as brown yellow powder. Mp = 205207 °C. 1 H NMR (D 2 O) #: 2.04-2.14 (m, 2H, vol.3

, 5-Trimethoxybenzylamino)propylamine hydrochloride (11i), vol.4

, Hydrochloride salt 11i was prepared from 10i in 87% yield as brown powder. Mp = 200-202 °C. 1 H NMR

, C-1); 43.5 (C-3), ES + HRMS, m/z: 255.1706 found, vol.36

, Methylbenzylamino)propylamine hydrochloride (11j)

, 31 (s, 3H, CH 3 ); 2.87-2.95 (m, 4H, H-1, H-3), Hydrochloride salt 11j was prepared from 10i in 98% yield as brown powder. Mp > 250 °C. 1 H NMR (DMSO-d 6 ) #: 1.99-2.04 (m, 2H, vol.2, p.50

, Hydrochloride salt 11k was prepared from 10k in 98% yield as tannish yellow powder, Mp >, vol.250

, °C. 1 H NMR (DMSO-d 6 ) #: 1.99-2.09 (m, 2H

. Hz, 62-7.66 (m, 2H, H-3', H-5', Ar); 8.22 (br s, 3H, NH 2 , HCl), vol.7, p.68

. , Ar), ES + HRMS, m/z: 199.1001 found, vol.130, p.35

, Chlorobenzylamino)propylamine hydrochloride (11l)

, H-2); 2.87-2.92 (m, 2H, H-1), Hydrochloride salt 11l was prepared from 10l in 94% yield as tannish yellow powder. Mp = 177179 °C. 1 H NMR (DMSO-d 6 ) #: 2.03-2.13 (m, 2H, vol.8, p.77

, Ar); 129.6 (C-4', Ar), vol.129

E. Hrms,

H. Nmr,

, H-3', H-5', Ar). 13 C NMR (D 2 O) #: 23.7 (C-2); 36.5 (C-1), vol.44

H. Nmr-;-m, 2. , and H. , 27 (br s, 3H, NH 2 , HCl), DMSO-d 6 ) #: 1.87-2.11 (m, 2H, vol.3

, Quinolin-8-yl)methylamino]propylamine hydrochloride (11o)

, Hydrochloride salt 11o was prepared from 10o in 98% yield as dark brown powder, pp.204-206

, 24 (br s, 3H, NH 2 , HCl); 8.59-8.62 (dd, 1H, J = 1.6, 8.3 Hz, H-4', Ar), vol.8, pp.5-9

H. Hz, 55 (br s, 1H, NH). 13 C NMR (DMSO-d 6 ) #: 23.7 (C-2), vol.9

, Ar); 126.8 (C-5', Ar); 128.2 (C-6', Ar), ES + HRMS, m/z: 238.1323 found, vol.128

H. Nmr,

5. Hz-;-m and H. , 46 (br s, 1H, NH). 13 C NMR (DMSO-d 6 ) #: 23.7 (C-2); 36.3 (C-1), ES + HRMS, m/z: 165.1390 found, vol.9

, Standard procedure for the preparation of ethyl !-amino 2-(1H-benzimidazol-2-yl)acrylate 12(a-d) by transamination from {3

, OCH 2 O), Ar, vol.49, issue.7

E. Hrms, , p.423, 2036.

, CH 2 CH 3 ); 1.962.01 (m, 2H, H-2'); 2.92-2.97 (m, 2H, H-3'); 3.61 (t, 2H, J = 6.7 Hz, H-1'); 3.73 (s, 3H, OCH 3 )

, 11 (s, 1H, =CH); 8.85 (br s, 1H, NH), vol.8, p.80

, 11.82 (br s, 1H, NH). 13 C NMR

, CH 3 ), Ar, vol.55, issue.2

, ES + HRMS, m/z: 409.2236 found, vol.166, pp.159-166

, Mp = 150-152 °C. 1 H NMR (DMSO-d 6 ) #: 1.30 (t, 3H, J = 7.0 Hz, CH 2 CH 3 ); 1.992.04 (m, 2H, H-2'); 2.98 (m, 2H, H-3'); 3.61 (m, 2H, J = 6.6 Hz, H-1'), Compound 12g was synthesized in 34% yield as tannish orange powder according to the standard procedure (precipitation in 3 mL of AcOEt, then reflux in AcOEt (10 mL) for 4 h under mixing at 500 rpm, and after filtration on a Büchner funnel, the insoluble compound 12g was rinsed with 8 x 1 mL of AcOEt), vol.1

. , OCH 3 ); 59.2 (CH 2 CH 3 ), Ar), vol.27, issue.4

, CH 2 CH 3 ); 2.00-2.04 (m, 2H, H-2'); 2.96-3.00 (m, 2H, H-3'); 3.61 (t, 2H, J = 6.5 Hz, H-1'); 3.74 (s, 6H, (OCH 3 ) 2 ), °C followed by mixing (500 rpm) for 6 h at 0 °C; and after filtration on a Büchner funnel, the insoluble compound 12h was rinsed with 3 x 1 mL of acetone). Mp = 166-168 °C. 1 H NMR (DMSO-d 6 ) #: 1.30 (t, 3H, J = 7.0 Hz, vol.8, p.17

, Compound 12i was synthesized in 15% yield as tannish yellow powder according to the standard procedure (precipitation in 2 mL of acetone, then reflux in acetone (6 mL) for 13 h under mixing at ! 26

3. , J. =-;-m, 2. , and H. , 98 (t, 2H, J = 8.1 Hz, H-3'); 3.60-3.62 (m, 2H, H-1'); 3.64 (s, 3H, OCH 3 ); 3.78 (s, 6H, 2 x OCH 3 ), rpm, and after filtration on a Büchner funnel, the insoluble compound 12i was rinsed with 7 x 1 mL of acetone). Mp =, vol.1

, mL of acetone, then reflux for 1 h under mixing at 500 rpm, and after filtration on a Büchner funnel, the insoluble compound 12j was rinsed with 10 x 1 mL of acetone)

2. and J. =. , 94 (s, 1H, =CH); 11.08 (br s, 1H, NH), Ar, vol.7, issue.2, pp.51-58

E. Hrms,

, Compound 12k was synthesized in 36% yield as orange powder according to the standard procedure (precipitation in 2 mL of acetone, and after filtration on a Büchner funnel, the insoluble compound 12k was rinsed with 10 x 1 mL of acetone), Mp = 178-180 °C. 1 H NMR

H. Hz and J. , 27 (br s, 1H, NH); 10.79 (br s, 1H, NH); 11.79 (br s, 1H, NH). 13 C NMR (DMSO-d 6 ) #: 14.6 (CH 2 CH 3 ); 27.5 (C2'), vol.7

, Ar); 141.7 (C-3a, C7a, Ar), ES + HRMS, m/z: 413.1742 found, vol.131, p.35

, Ethyl 2-(1H-benzimidazol-2-yl)-3-[3-(2-chlorobenzylamino)propylamino]acrylate (12l)

2. , H. ;-m, 2. , and H. , 63 (t, 2H, J = 6.6 Hz, H-1'), vol.3

, CH 3 ), vol.86

, Ar), vol.130, issue.9

, =CH); 166.6 (C=O, CO 2 Et), ES + HRMS, m/z: 413.1747 found, vol.153, p.35

, 12m) mixing (500 rpm) for 4 h at 0 °C; and after filtration on a Büchner funnel, the insoluble compound 12m was rinsed with 6 x 1 mL of acetone)

H. Hz, 27 (s, 2H, H-4'), vol.4

, 82 (br s, 1H, NH). 13 C NMR (DMSO-d 6 ) #: 14.7 (CH 2 CH 3 ), vol.10

C. and C. , Ar); 151.8 (C-2, Ar), ES + HRMS, m/z: 426.1911 found, vol.153, p.9, 1906.

, mL of Et 2 O and 1 mL of EtOH at 0 °C; and after filtration on a Büchner funnel, the insoluble compound 12m was rinsed with 5 x 1 mL of EtOH)

, 70 (br s, 1H, NH); 11.71 (br s, 1H, NH), vol.8, p.35

. , Ar); 140.8 (C-3a, C-7a, Ar), ES + HRMS, m/z: 380.2088 found, vol.124

. Mp, , pp.112-114

, CH 2 CH 3 ); 1.91-1.95 (m, 2H, H-2'); 2.89 (t, 2H, J = 5.4 Hz, H-3'); 3.61 (t, 2H, J = 6.8 Hz, H-1'), vol.2

, C-2'); 45.05 (C-3'); 46.2 (C1'), vol.28

C. and C. , Ar); 150.2 (C-2, Ar), ES + HRMS, m/z: 430.2246 found, vol.151, p.9

, Ethyl 2-(1H-benzimidazol-2-yl)-3-(3-benzylaminopropylamino)acrylate (12p)

, 2 mL of acetone, then reflux in acetone for 1 hour under mixing at 500 rpm, and after filtration on a Büchner funnel, the insoluble compound 12p was rinsed with 10 x 1 mL of acetone). Mp = 234-236°C. 1 H NMR (DMSO-d 6 ) #: 1.30 (t, 3H, J = 7.1 Hz, CH 2 CH 3 ); 2.002.05 (m, 2H, H-2'), vol.2

, 11.81 (br s, 1H, NH). 13 C NMR

, CH 3 ), vol.59

, Ar); 132.1 (C-1", Ar); 141.6 (C-3a, C7a, Ar), ES + HRMS, m/z: 379.2130 found, vol.128, p.9

, Ethyl 2-(1H-benzimidazol-2-yl)-3-(3-tert-butyloxycarbonylaminopropylamino)acrylate (13)

, ) in dry methylene chloride (8 mL) was added in one portion ethyl 3-dimethylamino-2-(1H-benzimidazol-2yl)acrylate 5 (0.1633 g, 0.63 mmol., 1 equiv.). Then the resulting reaction mixture was refluxed under vigorous magnetic stirring for 48 h. After cooling down to room temperature, the reaction mixture was concentrated under reduced pressure in a rotary evaporator. The crude residue was submitted to purification by preparative chromatography (Combi Flash R f 200 psi apparatus, detector UV 254 nm) on pre-packed column of alumina gel Puriflash Interchim (5 g, 32-63 µm, P max 22 bar) using a stepwise gradient of cyclohexane/AcOEt eluent from 99:1 to 90:10. Pooling and evaporation of solvents in vacuo gave the expected compound 13 which, was dried under high vacuum (10-2 Torr) at 25 °C for 1 h. White needles

2. and J. =. , d, 1H, J = 12.5 Hz, =CH); 10.93 (br s, 1H, NH); 11.03 (br s, 1H, NH). 13 C NMR (CDCl 3 ) #: 14.8 (CH 2 CH 3, vol.2

, CO); 82.2 (C=), vol.110

, Ethyl 3-(3-aminopropylamino)-2-(1H-benzimidazol-2-yl)acrylate hydrochloride (14)

, The resulting mixture was stirred at 500 rpm during 4 h at 25 °C. and was concentrated in a rotary evaporator under reduced pressure for elimination of volatile compounds. To the crude reaction mixture was added 2 mL of anhydrous Et 2 O and after triturating, the insoluble salt 14 was collected by filtration on a Büchner funnel (porosity N°4) and was dried under high vacuum (10-2 Torr) at 25 °C for 4 h and gave the desired compound 14 in 72% yield as white powder. 1 H NMR (D 2 O) #: 1.37 (t, 3H, 27 mmol., 1 equiv.) was solubilized in 2 mL of dry 1,4-dioxane at 25 °C under vigorous stirring (550 rpm) during 20 min. Then a solution of 6M HCl

, C-6); 130.0 (C-3a, C-7a)

, yl)acrylate (15) In a 10 mL glass tube (for microwave synthesis) were placed successively ethyl 3-(3aminopropylamino)-2-(1H-benzimidazol-2-yl)acrylate hydrochloride 14 (14.2 mg, 0.044 mmol., 1 equiv.), N,N-di-iso-propylethylamine DIPEA (8 µL, 6.1 mg, 0.0473 mmol., 1.075 equiv.), 3,4(methylenedioxy)benzaldehyde 8a (6.6 mg, 0.044 mmol., 1 equiv.) and 1 mL of dry methanol. The glass tube was sealed with a snap cap

, After microwave dielectric heating, the crude reaction mixture was allowed to cool down at room temperature and volatile compounds were eliminated in a rotary evaporator under reduced pressure. The desired aldimine 15 as yellowish viscous oil was dried under high vacuum (10-2 Torr) at 25°C for 20 min. and further used without purification, The reaction mixture was irradiated during 45 min. at 90 °C under vigorous magnetic stirring

H. Hz, 61 (s, 1H, =CH); 7.86 (br s, 1H, NH), vol.7

W. Akhtar, F. Khan, M. Verma, G. Shaquiquzzaman, M. Rizvi et al., Therapeutic evolution of benzimidazole derivatives in the last quinquennial period, Eur J Med Chem, vol.126, pp.705-753, 2017.

M. Gaba, M. Singh, S. Mohan, and C. , Benzimidazole: An emerging scaffold for analgesic and anti-inflammatory agents, Eur J Med Chem, vol.76, pp.494-505, 2014.

G. Yadav and S. Ganguly, Structure activity relationship (SAR) study of benzimidazole scaffold for different biological activities: A mini-review, Eur J Med Chem, vol.97, pp.419-443, 2015.

M. Dobbelstein and U. Moll, Targeting tumor-supportive cellular machineries in anti-cancer drug development, Nat Rev Drug Disc, vol.13, pp.179-196, 2014.

R. Kath and K. Blumenstengel, Bendamustine monotherapy in advanced and refractory chronic lymphocytic leukemia, J Cancer Res Clin Oncol, vol.127, pp.48-54, 2001.

P. Sharma, D. Thummuri, T. S. Reddy, K. R. Senwar, V. Naidu et al., New (E)-1-alkyl-1H-benzo[d] imidazol-2-yl)methylene)indolin-2-ones: synthesis, in vitro cytotoxicity evaluation and apoptosis inducing studies, Eur J Med Chem, vol.122, pp.584-600, 2016.

J. Wang, X. Wang, H. Li, J. D. Li, Y. Xu et al., Design, synthesis and biological evaluation of novel 5-fluoro-1H-benzimidazole-4-carboxamide derivatives as potent PARP-1 inhibitors, Bioorg Med Chem Lett, vol.26, pp.4127-4132, 2016.

A. Sharma, V. Luxami, and K. Paul, Purine-benzimidazole hybrids: synthesis, single crystal determination and in vitro evaluation of antitumor activities, Eur J Med Chem, vol.93, pp.414-422, 2015.

H. Varshney, A. Ahmad, A. Rauf, A. Sherwani, and M. Owais, Multistep synthesis of 1-[{(5alkenyl/hydroxyalkenylsubstituted)-1,3,4-oxadiazol-2-yl}-methyl]-2-methyl-1H-benzimidazole series and in vitro anti-cancer screening, SAR studies, Med Chem Res, vol.24, pp.944-953, 2015.

L. Shi, T. T. Wu, Z. Wang, J. Y. Xue, and Y. G. Xu, Discovery of N-(2-phenyl-1H-benzo [d]imidazol-5-yl)quinolin-4-amine derivatives as novel VEGFR-2 kinase inhibitors, Eur J Med Chem, vol.84, pp.698-707, 2014.

R. Brugidou, J. P. Bazureau, J. Hamelin, Z. Dahmani, and M. Rahmouni, Stereoselective synthesis of (2E) 3-amino-2-(1H-benzimidazol-2-yl)acrylate and symmetric bis-acrylates by transamination reactions, Het Chem, vol.10, pp.446-454, 1999.

M. Rahmouni, A. Derdour, J. P. Bazureau, and J. Hamelin, A new route to pyrimido[1,6a]benzimidazoles: Reactivity of activated 2-benzimidazoles with N-acyl imidates as !dielectrophiles under microwave irradiation, Tet Letters, vol.35, pp.60728-60729, 1994.

Z. Dahmani, M. Rahmouni, R. Brugidou, J. P. Bazureau, and J. Hamelin, A new route to %hetero !-enamino esters using a mild and convenient solvent-free process assisted by focused microwave irradiation, Tet Letters, vol.39, pp.1894-1896, 1998.

, Ultrasound and microwave: recent advances in organic chemistry, Research Signpost, 2011.

N. Ambeu, C. 'ta, C. D. Dago, W. Coulibaly, J. A. Mamyrbekova-bekro et al., Microwave assisted prospective synthesis of new 5-arylidene rhodanine derivatives bearing an 3-[(4-(3-aminopropyl)piperazin-1-yl)propyl] chain, Curr Microwave Chem, vol.3, pp.145-156, 2016.

N. Ambeu, C. 'ta, C. Dago, W. Coulibaly, J. A. Mamyrbekova-bekro et al., Microwave synthesis of new 3-(3-aminopropyl)-5-arylidene-2-thioxo-1,3-thiazolidine4-ones as potential Sr/Thr proteine kinase inhibitors, Med Chem Res, vol.25, pp.2940-2958, 2016.

C. D. Dago, N. Ambeu, C. 'ta, W. Coulibaly, Y. Bekro et al., Synthetic development of new 3-(4-arylmethylamino)butyl-5-arylidene-rhodanines under microwave irradiation and their effects on tumor cell lines and against protein kinases, Molecules, vol.20, pp.12412-12435, 2015.
URL : https://hal.archives-ouvertes.fr/hal-01187427

H. Brederek, G. Simchen, and W. Griebenow, Orthoamide, XXVI. Synthese und Reaktionen von 1,2bis(dialkylamino)äthylenen, Chem Ber, vol.107, pp.1545-1554, 1974.

M. Meziane, M. Rhamouni, J. Bazureau, and J. Hamelin, A new route to 1-oxo-2,3dihydropyrimido-[1,6-a]-benzimidazol-4-carboxylate from ethyl 2-(benzimidazol-2-yl)-3dimethylamino acrylate using solvent-free conditions, Synthesis, 1998.

N. Meddad, M. Rahmouni, A. Derdour, J. Bazureau, and J. Hamelin, Eco-friendly transamination and aza-annulation reactions : Solvent-free synthesis of new !-hetero "hydrazino acrylates and 1,2-dihydropyrazol-3-ones. Synthesis 581-584, 2001.

, Microwaves in Organic Chemistry, vol.3, pp.978-981, 2012.

K. Takagi, T. Aotsuka, H. Morita, and Y. Okamoto, Synthesis of pyrimidino[4,5b][1,5]benzodiazepin-2-ones and pyrimidino[1,6-a]benzimidazol-1-ones from 4ethoxycarbonylamino-1H-1,5-benzodiazpine-3-carbonitrile via 4-(2-aminoanilino)pyrimidin2(1H)-one-5-carbonitriles, J. Heterocycl Chem, vol.23, pp.1443-1449, 1986.

S. Rajappa, Nitroenamines: Preparation, structure and synthetic potential, Tetrahedron, vol.37, pp.1453-1463, 1981.

H. Nakabayashi, K. Taketssa, K. Miyano, T. Yamane, and J. Sato, Growth of human hepatoma cell lines with differentiated functions in chemically defined medium, Cancer Res, vol.42, pp.3858-3863, 1982.