2. Introduzione alla parte sperimentale
3.2. Caratteristiche chimico-fisiche e spettroscopiche de
- 6-bromo-2-(4-metossifenil)-H-imidazo[1,2-a]piridina, 18a - 6-bromo-2-fenil-H-imidazo[1,2-a]piridina, 18b
Il primo step della sintesi dei derivati eterociclici a nucleo imidazopi- ridinico prevede la formazione dell’eterociclo a partire da 2-ammino- 5-bromopiridina e dall’opportuno 2-bromoacetofenone, in rapporto equimolare.
10.00 mmol di 2-ammino-5-bromopiridina e 10.00 mmol dell’opportuno 2-bromoacetofenone, prodotti commerciali, sono me- scolati intimamente in un mortaio, trasferiti in un pallone e fatti rea- gire a fusione per circa 6-8 ore a una temperatura di 80°C. La misce- la è mescolata ogni tanto con una bacchetta di vetro.
Il termine della reazione è controllato mediante T.L.C. dalla quale si nota la scomparsa dei reagenti di partenza.
Il prodotto desiderato, sottoforma di solido giallo, è recuperato per cristallizzazione con MeOH.
N N Br
R
Caratteristiche chimico-fisiche
Composto R Resa Solvente di cri-stallizzazione P.f. (°C) Formula
18a OCH3 84% MeOH 280-285 C14H11BrN2O
Caratteristiche spettroscopiche Composto R 1H-NMR (DMSO-d(δ, ppm) 6) 18a OCH3 9,21 (s, 1H, Ar) 8,59 (s, 1H, Ar) 8,03-7,83 (m, 4H, Ar) 7,15 (d, 2H, Ar) 3,85 (s, 3H, OCH3) 18b H 9,24 (s, 1H, Ar) 8,69 (s, 1H, Ar) 8,03-7,86 (m, 4H, Ar) 7,63-7,52 (m, 3H, Ar)
- 6-(4-metossifenil)-2-(4-metossifenil)-H-imidazo[1,2-a]piridina, 20a - 6-(3,4-dimetossifenil)-2-(4-metossifenil)-H-imidazo[1,2- a]piridina, 20b - 6-(3,5-dimetossifenil)-2-(4-metossifenil)-H-imidazo[1,2- a]piridina, 20c - 2-(4-metossifenil)-6-fenil-H-imidazo[1,2-a]piridina, 20d - 6-(3,4-dimetossifenil)-2-fenil-H-imidazo[1,2-a]piridina, 20e - 6-(4-metossifenil)-2-fenil-H-imidazo[1,2-a]piridina, 20f
L’opportuno bromo derivato 18a,b è trasformato nei corrispondenti derivati metossilati 20a-f mediante reazione al microonde. In ciascu- na vial, contenente 10.00 mmol di bromoderivato, sono aggiunti: 15.00 mmol dell’opportuno acido fenilboronico (rapporto 1:1,5), 0,10 mmol di catalizzatore Tetrakis(trifenilfosfina)palladio (rapporto 1:0,01) e 2 mL di soluzione K2CO3 2M. la reazione è condotta al microonde
Biotage nelle seguenti condizioni: Power: 100 W Rampa: 1’ Tempo di reazione: 15’-20’ Temperatura: 100°C Pressione: 80 PSI Stirring: off Power max: on
Il termine della reazione è controllato mediante T.L.C.
Al grezzo è addizionata acqua ed è successivamente eseguita l’estrazione con AcOEt. La fase organica è seccata su MgSO4 ed eva-
N N R R1 R2 R3 20a: R=R2=OCH3 ; R1=R3=H 20b: R=R1=R2=OCH3 ; R3=H 20c: R=R1=R3=OCH3 ; R2=H 20d: R=OCH3 ; R1=R2=R3=H 20e: R=R3=H ; R1=R2=OCH3 20f: R=R1=R3=H ; R2=OCH3 Caratteristiche chimico-fisiche
Composto R R1 R2 R3 Resa Miscela eluente P.f. (°C) Formula
20a OCH3 H OCH3 H 38% A=3/E=7 205 C21H18N2O2
20b OCH3 OCH3 OCH3 H 22% A=3/E=7 139-144 C22H20N2O3
20c OCH3 OCH3 H OCH3 20% A=3/E=7 150 C22H20N2O3
20d OCH3 H H H 40% A=5/E=5 160 C20H16N2O
20e H OCH3 OCH3 H 54% A=3/E=7 161-163 C21H18N2O2
Caratteristiche spettroscopiche
Composto R R1 R2 R3 1H-NMR (DMSO-d6) ( ,ppm)
20a OCH3 H OCH3 H
8,79 (s, 1H, Ar) 8,26 (s, 1H, Ar) 7,90 (d, 2H, Ar) 7,53-7,68 (m, 4H, Ar) 7.00-7,10 (m, 4H, Ar) 3,82 (s, 6H, OCH3)
20b OCH3 OCH3 OCH3 H
8,82 (s, 1H, Ar) 8,27 (s, 1H, Ar) 7,92 (d, 2H, Ar) 7,56-7,63 (m, 2H, Ar) 7,22-7,31 (m, 2H, Ar) 7,00-7,10 (m, 2H, Ar) 3,87 (s, 3H, OCH3) 3,80 (s, 6H, OCH3)
20c OCH3 OCH3 H OCH3
8,90 (s, 1H, Ar) 8,28 (s, 1H, Ar) 7,93 (d, 2H, Ar) 7,61 (t, 2H, Ar) 7,07-6,68 (m, 2H, Ar) 6,88 (d, 2H, Ar) 6,57 (t, 1H, Ar) 3,88 (s, 6H, OCH3) 20d OCH3 H H H 8,88 (s, 1H, Ar) 8,30 (s, 1H, Ar) 7,93 (d, 2H, Ar) 7,78-7,40 (m, 7H, Ar) 3,80 (s, 3H, -OCH3)
20e H OCH3 OCH3 H
8,84 (s, 1H, Ar) 8,38 (s, 1H, Ar) 7,99 (d, 2H, Ar) 7,62 (s, 2H, Ar) 7,46 (t, 2H, Ar) 7,36-7,22 (m, 3H, Ar) 7,06 (d, 1H, Ar) 3,87 (s, 3H, OCH3) 3,80 (s, 3H, OCH3) 20f H H OCH3 H 8,80 (s, 1H, Ar) 8,38 (s, 1H, Ar) 7,98 (d, 2H, Ar) 7,67-7,32 (m, 7H, Ar) 7,06 (d, 2H, Ar) 3,81 (s, 3H, OCH3)
- 4-(2-(4-idrossifenil)-H-imidazo[1,2-a]piridin-6-il)fenolo, 21a - 4-(2-(4-idrossifenil)-H-imidazo[1,2-a]piridin-6-il)benzene-3,4- diolo, 21b - 4-(2-(4-idrossifenil)-H-imidazo[1,2-a]piridin-6-il)benzene-3,5- diolo, 21c - 4-(2-(4-idrossifenil)-H-imidazo[1,2-a]piridin-6-il)benzene, 21d - 4-(2-fenil-H-imidazo[1,2-a]piridin-6-il)benzene-3,4-diolo, 21e - 3-metossi-4-(2-fenil-H-imidazo[1,2-a]piridin-6-il)fenolo, 21f - 4-(2-fenil-H-imidazo[1,2-a]piridin-6-il)fenolo, 21g
10.00 mmol dell’opportuno metossiderivato 14a-f sono solubilizzati in diclorometano anidro. Alla soluzione risultante è aggiunta goccia a goccia, in atmosfera di azoto e alla temperatura di -15°C, una solu- zione di BBr3 (15.00 mmol). I reagenti sono lasciati reagire a tempera-
tura ambiente, sotto agitazione, per circa 20 ore. Terminata la reazio- ne l’eccesso di BBr3 è degradato con acqua. Il solido è raccolto me-
diante filtrazione sotto vuoto e cristallizzato da opportuno solvente.
N N R1 R2 R3 R 21a: R=R2=OH ; R1=R3=H 21b: R=R1=R2=OH ; R3=H 21c: R=R1=R3=OH ; R2=H 21d: R=OH ; R1=R2=R3=H 21e: R=R3=H ; R1=R2=OH 21f: R=R3=H ; R1=OCH3 ; R2=OH 21g: R=R1=R3=H ; R2=OH
Caratteristiche chimico-fisiche Com- posto R R1 R2 R3 Resa Solv. cri- stal. P.f. (°C) Formula 21a OH H OH H 31% EtOH 335 C19H14N2O2 21b OH OH OH H 26% EtOH 330 C19H14N2O3 21c OH OH H OH 22% --- 360 C19H14N2O3 21d OH H H H 82% --- 315 C19H14N2O 21e H OH OH H 83% EtOH 270 C19H14N2O2 21f H OCH3 OH H 61% MeOH 280 C20H16N2O2 21g H H OH H 44% MeOH 320-325 C19H14N2O
Caratteristiche spettroscopiche Composto R R1 R2 R3 1H-NMR (DMSO-d6) (δ,ppm) 21a OH H OH H 10,15 (s, 1H, OH, exc) 9,85 (s, 1H, OH, exc) 9,10 (s, 1H, Ar) 8,53 (s, 1H, Ar) 8,18 (d, 2H, Ar) 7,90 (d, 2H, Ar) 7,80 (d, 2H, Ar) 7,62 (d, 2H, Ar) 7,00-6,90 (m, 4H, Ar) 21b OH OH OH H 10,15 (s, 1H, OH, exc) 9,40 (s, 1H, OH, exc) 9,20 (s, 1H, OH, exc) 9,05 (s, 1H, Ar) 8,55 (s, 1H, Ar) 8,13 (d, 1H, Ar) 7,90 (d, 1H, Ar) 7,80 (d, 2H, Ar) 7,17-6,90 (m, 5H, Ar) 21c OH OH H OH 10.18 (s, 1H, OH, exc) 9,60 (s, 1H, OH, exc) 9.10 (s, 1H, OH, exc) 8,60 (s, 1H, Ar) 8,10 (d,1H, Ar) 7,95 (d, 1H, Ar) 7,80 (d, 2H, Ar) 7,00 (d, 2H, Ar) 6,60 (s, 2H, Ar) 6,38 (s, 1H, Ar) 21d OH H H H 10,15 (s, 1H, OH, exc) 9,20 (s, 1H, Ar) 8,55 (s, 1H, Ar) 8,20 (d, 1H, Ar) 7,95 (d, 1H, Ar) 7,80 (t, 4H, Ar) 7,60 (t, 2H, Ar) 7,50 (t, 2H, Ar) 7,00 (d, 2H, Ar) 21e H OH OH H 9.45 (s, 1H, OH, exc) 9,30 (s, 1H, OH,exc) 9,08 (s,1H, Ar) 8,73 (s,1H, Ar) 8,12-8,18 (dd, 1H, Ar) 7,94-8,00 (t, 3H, Ar) 7.62 (t, 2H, Ar) 7,53 (t, 1H, Ar) 7,17 (d, 1H, Ar) 7,08 (dd, 1H, Ar) 6,92 (d, 1H, Ar) 21f H OCH3 OH H 8,99 (s, 1H, OH, exc) 8,64 (s, 1H, Ar) 8,14 (d, 1H, Ar) 7,90 (d,3H, Ar) 7,57 (d, 3H, Ar)
7,09 (t, 3H, Ar) 6,90 (d, 1H, Ar) 3,14 (s, 3H, OCH3) 21g H H OH H 9,98 (s, 1H, OH, exc) 9,14 (s, 1H, Ar) 8,74 (s, 1H, Ar) 8,21 (d, 1H, Ar) 7,97 (d, 3H, Ar) 7,61 (t, 5H, Ar) 6,94 (d, 2H, Ar)
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