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C. Arom, HRMS-ESI: m/z

H. Substrate, J. =. , and J. =. , brown solid (151 mg, 94%) 1 H NMR (300 MHz, DMSO-d 6 ) ? (ppm) = 1.65 (bs, 2H, NH 2 ), 2.76-2.90 (m, 4 H 11.93 (bs, 1 H, NH). 13 C NMR (75 MHz, DMSO-d 6 ) ? (ppm) = 29, pp.3-5

. Di, 1H-indol-3-yl)ethanamine

H. Substrate, J. =. , and J. =. , Procedure A; Compound 110: brown solid (209 mg, 76%) 1 H NMR (300 MHz, MeOD-d 4 ) ? (ppm) = 3.43 (d, J =, vol.2, issue.79, pp.2-3048

. Hz, C q ) HRMS-ESI: m/z, C NMR (75 MHz CH) CH) CH), 122.5 (2 CH) CH), pp.276-276, 1495.

. Substrate, 1H-indol-3-yl)-2-nitro-ethyl]-chromen-2-one 66; Procedure A; Compound 111: brown solid (272 mg, 85%). 1 H NMR (400 MHz, MeOD-d 4 ) ? (ppm) = 3, pp.4-7

J. =. Hz, H. , and J. =. , 95 (t, 1 H, J = 7, 7.26 (d, 1 H, J = 8.1 Hz, H arom ) Hz, H arom ) 13 C NMR (100 MHz, MeOD-d 4 ) ? (ppm) = 32CH), 2006.

. Substrate, Procedure A; Compound 106: brown solid (218 mg, 78%) 1 H NMR (400 MHz, DMSO-d 6 ) ? (ppm) = 3.35 (masked, 1 H, CH), 3.59-3.63 (m + s, 4 H, CH+CH 3 ), 3.70 (dt, 1 H, J = 8.7 Hz, J = 1.0 Hz, CH), H, J = 7.9 Hz, H arom ), 7.51 (d, 1 H, J = 7.9 Hz, H arom ), 8.19 (s, 1 H, NH), 11.00 (s, 1 H, NH). 13 C NMR (100 MHz, DMSO-d 6 ) ? (ppm) = 37.0 (CH)CH)CH), pp.2-3

. Substrate, 1H-indol-3-yl)-2-nitro-ethyl]-2-methoxymalonic acid dimethyl ester 55; Procedure A; Purification: flash chromatography (EtOAc 100% to EtOAc, Compound, vol.9, issue.112, pp.2-3

H. Hz and J. =. , 22 (bs, 1 H, NH) 13 C NMR (75 MHz, CDCl 3 ) ? (ppm) = 42.6 (CH), 119.7 (CH), pp.311-311, 1002.

H. Substrate and J. =. , Procedure A; extraction with HCl 0.5 M; Compound 113: clear brown solid (78 mg, 63%) 1 H NMR (300 MHz, DMSO-d 6 ) ? (ppm) = 3.32 (masked, 1 H, CH), 3.47 (d, 1 H, J = 10.5 Hz, CH), 10.97 (s, 1 H, NH). 13 C NMR (75 MHz, DMSO-d 6 ) ? (ppm) = 37.0 (CH), pp.5-6

. Substrate, Procedure A; Purification: the organic layer was treated with Et 2 O/HCl 2 M (0.8 ml) Compound 115: hydrochloride salt, white solid (112 mg, 68%) 1 H NMR (300 MHz, MeOD-d 4 ) ? (ppm) = 0, (m, 2 H, CH 2 ), 2.93 (t, 2 H, J = 7.5 Hz, CH 2 NH 3 + ). 13 C NMR (75 MHz, MeOD-d 4 ) ? (ppm) = 14, pp.1-114

H. Substrate and J. =. , Procedure A; Compound 117: brown oil (200 mg, 98%) 1 H NMR (400 MHz, CD 2 Cl 2 ) ? (ppm) = 1, pp.2-3

C. Nmr, CDCl 3 ) ? (ppm) = 31, MHz, vol.5, issue.343 21, p.59

. Substrate, 1 H NMR (300 MHz CDCl 3 ) ? (ppm) = 100, CDCl 3 ) ? (ppm) = 4.20 (bs, 2 H, NH 2 ) CH) CH) MS (ESI) m/z 119, pp.4-121

. Substrate, 1 H NMR (400 MHz, CDCl 3 ) ? (ppm) = 3.84 (s, 3 H, CH 3 Hz, H arom ). 13 C NMR (100 MHz, CDCl 3 ) ? (ppm) = 51, CH) CH)

. Mhz, CDCl 3 ) ? (ppm) = 51

. Substrate, Compound 101: brown solid (100 mg, 92%) 1 H NMR (300 MHz, DMSO-d 6 ) ? (ppm) = 4.37 (bs, 44 (d, 2 H, J = 8.7 Hz, H arom ), 6.51 (d, 2 H, J = 8.7 Hz, H arom ), 8.39 (bs, 1 H, OH). 13 C NMR (75 MHz, DMSO-d 6 ) ? (ppm) = 115, pp.4-131

. Substrate, Purification: the organic layer was treated with Et 2 O/HCl 2 M (0.6 ml) Compound 23: hydrochloride salt, white solid (128 mg, 88%). 1 H NMR (300 MHz, Procedure B, vol.7, issue.46, pp.4-134

. Substrate, CDCl 3 ) ? (ppm) = 2.50 (s, 3 H, CH 3 13 C NMR (75 MHz, CDCl 3 ) ? (ppm) = 26 MS (ESI) m/z 136 General procedures for deoxygenation General procedure A In a round bottom flask, to a solution of ketone (1 mmol) and Pd/C 5 % wt (50% in water) (212 mg, 0.1 mmol, 10 mol%) in CPME (1 mL) was added a mixture of sodium hypophosphite monohydrate (3 mmol, Procedure A; Compound 145: white solid (120 mg, 89%). 1 H NMR (300 MHz11 (bs, 2 H, NH 2 ), 6.63 (d, 2 H, J = 8.7 Hz, H arom ), 7.78 (d, 2 H, J = 8.7 Hz, H arom ) CH) CH) hypophosphorous acid 50% in water (1 mmol) in water (2 mL). The reaction mixture was sonicated between 2 and 5 hours. After dilution in CH 2 Cl 2 (10 mL), water (10 mL) was added. The aqueous phase was extracted with CH 2 Cl, pp.4-144

H. Substrate and J. =. , Compound 145b: brown liquid (105 mg, 86%) 1 H NMR (300 MHz, CDCl 3 ) ? (ppm) = 1.22 (t, 3 H, J = 7.5 Hz, CH 3, Hz, H arom ). 13 C NMR (75 MHz, CDCl 3 ) ? (ppm) = 16.0 (CH 3 CH) CH), pp.4-145

. Substrate, Procedure B; reaction time: 2 h; conversion: >99% Compound 155b: colorless liquid (121 mg, 88%) 1 H NMR (300 MHz, CDCl 3 ) ? (ppm) = 1.28 (t, 3 H, pp.4-15518

. Mhz, CDCl 3 ) ? (ppm) = 16, CH) CH)

. Substrate, Compound 156b: colorless liquid (131 mg, 80%) 1 H NMR (300 MHz, CDCl 3 ) ? (ppm) = 1.24 (t, 3 H, J = 7.5 Hz, CH 3 Hz, H arom ). 13 C NMR (75 MHz, CDCl 3 ) ? (ppm) = 15, CH) CH), pp.89-52, 1925.

. Substrate, Procedure B; reaction time 5 h; conversion: >99%; ratio a/b: 0/100; Compound 157b: GC yield with internal standard: dodecane (83%) GC: ZB-5-MS, injection temperature: 250°C, detection temperature: 280°C, column temperature, pp.4-157

H. Substrate and J. =. , Procedure B; reaction time: 1.5 h; conversion: >99%; ratio a/b: 0/100; Compound 158b: brown solid (116 mg, 95%). 1 H NMR (300 MHz, CDCl 3 ) ? (ppm) = 1, J =, vol.22, issue.83, pp.4-15859

H. Hz and J. =. , 3 Hz, H arom ) 13 C NMR (75 MHz, CDCl 3 ) ? (ppm) = 16, CH) CH)

. Hz, 13 C NMR (75 MHz, CDCl 3 ) ? (ppm) = 15

. Substrate, Procedure C in sealed tube with NaH 2 PO 2 (6 equiv) and H 3 PO 2 (2 equiv); time: 16 h, conversion: >99%; ratio a/b: 0/100; purification: precipitation with HCl, M) in Et 2 O (2 mL); Compound 161b: white solid (111 mg, 65%). 1 H NMR (300 MHz, CD 3 OD-d 4 ) ? (ppm) = 1, pp.4-1612266

H. Arom-hz, 13 C NMR (75 MHz, CD 3 OD-d 4 ) ? (ppm) = 16, CH) CH)

. Substrate, trifluoromethyl)acetophenone 162; Procedure C; conversion: >99%; ratio a, p.4

. Substrate, Procedure C; conversion: 89%; ratio a/b: 0/100; purification: flash chromatography (pentane 100%); Compound 163b: clear liquid (117 mg, 75%). 1 H NMR (300 MHz, pp.1-163

. Substrate, Compound 164b: liquid (141 mg, 90%) 1 H NMR (300 MHz, CDCl 3 ) ? (ppm) = 1.20 (t, 3 H, pp.2-1646749

H. Substrate and J. =. , Compound 166b: yellow solid (153 mg, 85%) 1 H NMR (300 MHz, CDCl 3 ) ? (ppm) = 2.54 (s, 3 H, CH 3 ), 3.94 (s, 2 H, Hz, H arom ). 13 C NMR (75 MHz, CDCl 3 ) ? (ppm) = 21, pp.9-11

. Substrate, Compound 167b: white solid (139 mg, 83%) 1 H NMR (300 MHz, CDCl 3 ) ? (ppm) = 4.04 (s, 2 H37 (m, 4 H, H arom ). 13 C NMR (75 MHz, CDCl 3 ) ? (ppm) = 42, CH) CH) CH), pp.31-38

. Substrate, Procedure C; conversion: >99% Compound 168b: grey solid (83 mg, 55%) 1 H NMR (300 MHz, CDCl 3 ) ? (ppm) = 3.66 (s, 2 H (m, 5 H, H arom ) 13 C NMR (75 MHz, CDCl 3 ) ? (ppm) = 41, CH) CH), p.71

. Substrate, 2-trifluoro acetophenone 169; Procedure A; reaction time: 3 h; conversion: >99%; ratio a/b: 100/0, p.79

. Mhz, CDCl 3 ) ? (ppm) = 1.41 (t, 3 H, J = 7.5 Hz, p.90

. Substrate, purification: flash chromatography (pentane 100%) Compound 172b: white solid (92 mg, 62%) 1 H NMR (400 MHz (m, 1 H, H arom ), 7.48 (m, 1 H, H arom ). 13 C NMR (100 MHz, CDCl 3 ) ? (ppm) = 12, CDCl 3 ) ? (ppm) = 1.34 (t, 3 H, J = 7.5 Hz, CH 3 ), 2.80 (qd, 2 H, J = 1.0 Hz, J = 7.5 Hz Hz, H arom ), 7.20 (td, 1 H, J = 1.3 Hz, J = 7.2 Hz, pp.2-25, 2002.

. Substrate, h; conversion: >99%; Compound 155c: white solid (116 mg, 82%) 1 H NMR (300 MHz, CDCl 3 ) ? (ppm) = 3.81 (s, 3 H, OCH 3 ), CH) CH), pp.4-155

. Substrate, procedure for deuteration; reaction time: 16 h; conversion: >99%; Compound 156c: white solid (131 mg, 77%) 1 H NMR (300 MHz, CDCl 3 ) ? (ppm) = 3, (d, 2 H, J = 8.4 Hz, H arom ), 7.95 (d, 2 H, J = 8.4 Hz, H arom ). 13 C NMR (75 MHz, CDCl 3 ) ? (ppm) = 14, 1925.

J. =. Hz, 9 Hz, CH)

. Hz, C q ) MS (QTOF) m/z, CH) CH), p.3

.. Heck-matsuda, Optimisation et application de la réaction de, p.139

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P. Positionnement-du and . Dans-ce-chapitre, isatines conduira à des spirotétrahydro-?-carbolines (spiroTHBC) inédites par réaction de Pictet-Spengler (Schéma 58) Cette transformation est très intéressante car elle crée plusieurs liaisons (liaisons carbone-azote puis carbone-carbone), et permet de synthétiser des structures difficilement accessibles par d'autres voies. Cette réaction a fait l'objet de nombreuses études, mais peu de publications décrivent la réactivité entre tryptamines et isatines. Un des objectifs de ce chapitre est de trouver la meilleure méthode pour obtenir les spirotétrahydro-?-carbolines potentiellement anti-paludiques. Dans un second temps, la substitution directe de la 5- aminoisatine 15 sera étudiée pour accéder à une plus large diversité fonctionnelle

S. E. O-'connor and J. J. Maresh, Spengler est une des méthodes les plus employées pour la synthèse de tétrahydro-?-isoquinoléines (THBQ) et de tétrahydro-?-carbolines (THBC) 150 à partir d'une ?-éthylamine aromatique (ou d'une tryptamine dans le cas des tétrahydro-?carbolines ) et d'un composé carbonylé Elle tient son nom de A. Pictet et T. Spengler qui en 1911 ont décrit la synthèse de la tétrahydro-?-isoquinoléine 175 par réaction de la ?phényléthylamine 174 sur le diméthoxyméthane en milieu acide (Schéma 59). 151 La première 150 a), Bibliographie sur la réaction de Pictet-Spengler 2.1. Généralités La réaction de Pictet. c) K. Pulka, pp.1797-1842, 1995.

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DOI : 10.1016/j.tet.2005.04.022

. Plasmodium-falciparum-et-un-premier-résultat-très-encourageant-a-Été-obtenu, Afin d'étendre l'étude des familles de ces composés, une nouvelle méthode de fonctionnalisation des isatines a aussi été mise au point, et a permis de synthétiser une famille d'isatines via le sel de diazonium provenant de la 5-aminoisatine. Ces motifs isatines ont été fontionnalisés par des alcènes substitués et ont été obtenus avec de bons rendements (53 à 98%), Ces composés devront être utilisés pour la synthèse de nouvelles spiroTHBC de la même famille que le composé 217 ayant donné les meilleurs résultats biologiques

. Substrates, 16 h; beige solid; yield = 99% : mp 171.2-172.4°C (Et 2 O, dec); IR 3252 (bs, 1H, NH), H NMR (400 MHz, DMSO-d 6 ) ? (ppm) = 2.72-2.86 (m, 2 H), pp.681-18898, 1111.

H. Hz, J. =. , and J. =. , 43 (s, 1 H, NH), 10.47 (s, 1 H, NH) 13 C NMR (100 MHz, DMSO-d 6 ) ? (ppm) = 21, 7.6 Hz, H arom ), 7.46 (d, 1 H, J = 7.6 Hz, H arom ), p.61, 2001.

. Substrates, 16 h; beige solid; yield = 98% : mp > 260°C (Et 2 O, dec); IR 1716, H NMR (400 MHz, DMSOd 6 ) ? (ppm) = 2.72 (m, 1 H), pp.536-179, 1201.

J. =. Hz and J. =. , 49 (s, 1 H, NH), 10.58 (s, 1 H, NH) 13 C NMR (100 MHz, DMSO-d 6 ) ? (ppm) = 21, 121.3 (CH)

. Amino, -tetrahydrospiro[?-carboline-1,3'-indol]-2'(1'H)-one (186e), 2009.

H. Substrates and J. =. , ethylamine 110, isatine; time: 16 h; flash chromatography; orange solid; yield = 41% : mp 207-209 °C (Et 2 O, dec.); IR 1716 533 cm -1 ; 1 H NMR (400 MHz, DMSO-d 6 ) ? (ppm) = 3, 1H), 3.73 (m, 1 H), 4.62 (m, 1 H), 6.67 (t, 1 H, J = 7.4 Hz, p.829297, 1093.

H. Hz, 05 (t, 1 H, J = 7.5 Hz, H arom ), 7.09 (s, 1 H, H arom )

H. Hz and J. =. , 50 (s, 1 H, NH), 10.59 (s, 1 H, NH), 10.83 (s, 1 H, NH) 13 C NMR (100 MHz, DMSO-d 6 ) ? (ppm) = 31.2 (CH), 118.7 (CH) CH), pp.61-65

. Substrates, 16 h; flash chromatography; orange solid; yield = 44% : mp 211.8-213.2°C (Et 2 O, dec) 533 cm -1 ; 1 H NMR (500 MHz, DMSO-d 6 ) ? (ppm) = 3, p.669903, 1093.

H. Hz and J. , 13 (d, 1 H, J = 2.2 Hz, p.20

H. Mhz and J. =. , 19 (s, 3 H, CH 328 (s, 3 H, CH 3, Hz), 3.68 (dd, 1 H, J = 6.9 Hz, J = 12.9 Hz), p.356168

H. Hz and J. =. , 08 (s, 1 H16 (d, 1 H, J = 8.1 Hz66 (d, 1 H, J = 7.8 Hz, H arom ), 10.48 (s, 1 H, NH), 10.54 (s, 1 H, NH), 10.84 (s, 1 H, NH) 13 C NMR (100 MHz, DMSO-d 6 ) ? (ppm) = 16, 111.1 (CH), 111.5 (CH), pp.83-89

. Substrates, 2-bis-(1H-indol-3-yl)-ethylamine 110, nitroisatine; time: 16 h; flash chromatography; orange solid; yield = 45%, 8°C (Et 2 O, dec); IR 3409, pp.7-236, 1095.

. Hz, 36 (d, 1 H, J = 8.1 Hz00 (s, 1 H, H arom )65 (s, 1 H, NH), 10.87 (s, 1 H, NH), 11.29 (s, NH) 13 C NMR (100 MHz, DMSO-d 6 ) ? (ppm) = 31, dd, 1 H, J = 8.8 Hz, J = 2.3 Hz, H arom ) 110.3 (CH, pp.31-61

. Phenyl, 9-tetrahydrospiro[?-carboline-1,3'-indol]-2'(1'H)-one (215a)

. Phenyl, 9-tetrahydrospiro[?-carboline-1,3'-indol]-2'(1'H)-one (215b)

H. Hz and J. =. , 25 (m, 1 H, H arom ), 7.29-7.34 (m, 5 H, H arom ), 10.63 (s, 1 H, NH), 10.71 (s, 1 H, NH). 13 C NMR (100 MHz, DMSO-d 6 ) ? (ppm) = 40, CH), pp.97-61

. Phenyl, ,9-tetrahydrospiro[?-carboline-1,3'-indol]-2'(1'H)-one (215c), 2004.

. Phenyl, 9-tetrahydrospiro[?-carboline-1,3'-indol]-2'(1'H)-one

. Substrates, 1H-Indol-3-yl)propylamine 107, nitroisatine; time: 24 h; flash chromatography; orange solid; yield = 82%; a minor 1 H NMR (400 MHz, DMSO-d 6 ) ? (ppm), J =, vol.6, issue.3, p.2

H. and J. Hz, 08-3.24 (m, 2 H, CH dia a+b), 3.41 (bs, 1 H, NH dia a+b), 3.65 (dd, 1 H, pp.96-103

. Hz, 13 (s, 1 H19 (s, 1 H, NH dia b) 13 C NMR (100 MHz, DMSO-d 6 ) ? (ppm) =18.6 (CH 3 dia b), CH dia b), 45.8 (CH 2 dia a), pp.582831-133

. Amino-spiro, 05 g, 8.7 mmol) was dissolved in MeOH (20 mL) and stirred with Pd/C 5% (1.8 g, 0.87 mmol, 0.1 eq) under H 2 atmosphere, during 8 hours. The mixture was filtered in Celite and evaporated to provide 197 as a pur white solid (1.75 g, 98%). 1 H NMR (300 MHz, DMSO-d 6 ) ? (ppm, 4.92 (bs, 2 H, NH 2 ), 6.52 (d, 2 H, J = 1.3 Hz, H arom ), 6.60 (s, 1 H, H arom ), 9.98 (bs, 1 H, NH). 13 C NMR (75 MHz, DMSO-d 6 ) ? (ppm) = 65 132.1 q )

. Aminoisatine, 92 g, 10 mmol) was dissolved in ethanol at 60°C (100 mL), and reduced iron powder (3.36 g, 60 mmol) was added Concentrated hydrochloric acid (10 mL) was added After 1 hour of reaction, the reaction mixture was treated with a saturated solution of sodium carbonate NaHCO 3 to pH 8 and extracted with EtOAc (5 x 200 mL) The combined organic layers were dried (MgSO 4 ) and evaporated to provide 15 as violet solid (1.34 g, 83%). 1 H NMR (300 MHz, DMSO-d 6 ) ? (ppm) = 5.07 (bs, pp.42816-53

J. =. Hz, 3 Hz, H arom ), 10.59 (bs, 1 H, NH). 13 C NMR (75 MHz, DMSO-d 6 ) ? (ppm) =

. Substrates, CuCN (1 eq) KCN (5 eq); Procedure B in MeCN at 60°C for 17 hours. The crude residue was recrystallised in cyclohexane, CH 2 Cl 2 (8/2) to provide compound 203 as an orange solid (74 mg, 33 %) : 1 H NMR (400 MHz, DMSO-d 6 ) ? (ppm) = 1, pp.5-70

. Substrates, Procedure A; Compound 210: red solid (224 mg, 97%). 1 H NMR (300 MHz, DMSO-d 6 ) ? (ppm) = 3.71 (s, 3 H, CH 3, J =, vol.6, issue.161, pp.5-1562

C. Hz, 93 (d, 1 H, J = 8.1 Hz, J =, vol.6, issue.161

C. Hz, 91 (d, 1 H, J = 1.7 Hz

J. =. Hz, 26 (s, 1 H, NH) 13 C NMR (100 MHz, DMSO-d 6 ) ? (ppm) = 51

H. Hz and J. , 44 (d, 1 H, J = 15

J. =. Hz and N. , 98 (d, 1 H, J = 1.5 Hz 13 C NMR (100 MHz, DMSO-d 6 ) ? (ppm) = 34, 123.7 (CH)

N. Substrates, CuBr (1 eq) CuBr 2 (1 eq) Procedure B; Compound 207: red solid (235 mg, 87%). 1 H NMR (300 MHz, DMSO-d 6 ) ? (ppm), pp.5-49

. Substrates, methyl acrylate; Procedure A; flash chromatography, Compound 209: red solid (179 mg, 65%). 1 H NMR (300 MHz, DMSO-d 6 ) ? (ppm) = 3.71 (s, 3 H, pp.5-9

. Substrates, Compound 213: yellow solid (178 mg, 62%) 1 H NMR (300 MHz, DMSOd 6 ) ? (ppm) = 2.92 (s, 3 H, CH 3 ), 3.15 (s, 3 H, CH 3 ), 4.29-4.37 (m, 4 H, CH 2 ), 6.85 (d, 1 H, J = 8.1 Hz (bs, 1 H, NH). 13 C NMR (75 MHz, DMSO-d 6 ) ? (ppm) = 35, Procedure A; flash chromatographyCH), 143.8 q ), pp.5-64, 1962.

. Michael, réduction de la fonction nitro en amine et cyclisation de Pictet-Spengler. En parallèle une méthode de fonctionnalisation des isatines intervenant lors de la réaction de Pictet- Spengler a été étudiée

. Dans-un-premier and . Temps, -nitrovinyl)indole a été étudiée Après optimisation des conditions, la réaction est réalisée sans protection préalable du noyau indole, en présence d'une base catalytique et sous activation ultrasons. Ces conditions ont permis l'addition de différents méthylènes activés avec des rendements compris entre 55% et 99% (Schéma 83). D'autres additions 1,4 ont été explorées telles que la réaction de Friedel-Crafts ou l'addition d'organomagnésiens