Scheme 49. Summary of the performed Suzuki-Miyaura coupling
7.1 Synthesis of phorbazoles analogues
7.1.1 General procedure for protection of the hydroxybenzaldehyde with tosyl group
Compound 1 and 0.4 mol % of DMAP were dissolved in DCM (10 mL per 1 g of compound 1).
Et₃N (4.5 mL per 1 g of 1) was added and the solution was cooled with stirring to 0 ⁰C.
Tosylchloride was suspended in DCM (2 mL per 1 g tosylchloride) and added dropwise to the solution. The mixture was stirred for 1 hour. A proper amount of water was added. The organic layer was separated, washed 2 times with 1 M HCl and 2 times with brine solution, dried over MgSO₄, filtered and the solvent evaporated. The crude was purified by
recrystallization using 15 % ethanol/water and dried.
7.1.1.1 3-Formylphenyl-4-methylbenzenesulfonate (2a)
3-Formylphenyl-4-methylbenzenesulfonate 2a (20.3 g, 73 mmol, 89 %) was prepared from 3-hydroxybenzaldehyde 1a (83 mmol) as pale yellow crystals. TLC;Rf=0.33 (30%
EA/heptane).1H NMR (CDCl₃, 400 MHz) δ = 9.93 (S,1H) , 7.78 (d, J = 7.6 Hz ,1H) , 7.72 (d, J = 7.6 Hz, 2H), 7.49 (t, J= 8 Hz, 1H) , 7.47 (s, 1H), 7.33 (d, J= 8 Hz , 2H) , 7.30 (m, 1H), 2.46 (s, 3H).
13C NMR (CDCl₃, 400 MHz) δ = 190.6, 150.2, 145.8, 137.9, 132.0, 130.4, 129.9, 128.5, 128.4, 128.2, 123.0, 21.7. HRMS (ESI) m/z: [M+H]⁺ calculated for C₁₄H₁₁O₄S [M+H]⁺ 275.0378, found 275.0383.
TsCL, Et₃N, DMAP, 0 ⁰C /DCM , 1h
45
7.1.1.2 2-Formylphenyl-4-methylbenzenesulfonate (2b)
2-Formylphenyl-4-methylbenzenesulfonate 2b (21 g, 76 mmol, 93 %) was prepared from 2-hydroxybenzaldehyde 1b (83 mmol) as pale yellow crystals. TLC;Rf=0.33 (30%
EA/heptane). 1H NMR (CDCl₃, 400 MHz) δ = 9.99 (S,1H), 7.87 (dd, J = 2,8 Hz, 1H) , 7.71 (d, J = 8 Hz, 2H), 7.59 (m, 1H) , 7.40 (t, j=8 Hz, 1H), 7.34 (d, J = 8 Hz, 2H) , 7.22 (d, j = 8 Hz, 1H), 2.46 (s, 3H). 13C NMR (CDCl₃, 400 MHz) δ = 187.3, 151.2, 146.3, 135.3, 131.4, 130.1, 129.3, 128.6, 128.5, 127.5, 123.8, 21.8. HRMS (ESI) m/z: [M+H]⁺ calculated for C₁₄H₁₁O₄S 275.0378, found 275.0384.
7.1.2 Modified procedure for oxazole synthesis by TosMIC.
Compound 2 and 1.1 eq. of TosMIC were dissolved in DME (5 mL per 1 g of 2). 1.1 eq. of DBU was added and the mixture was refluxed for 2-3 hours. Water was added and the organic layer was separated and washed 3 times with brine solution, dried over MgSO₄, filtered and the solvent was evaporated. The crude was purified by column chromatography using EA/pentane as eluent in an appropriate ratio to yield the corresponding oxazole derivatives.
7.1.2.1 3-(Oxazol-5-yl)phenyl-4-methylbenzenesulfonate (3a)
3-(Oxazol-5-yl)phenyl 4-methylbenzenesulfonate 3a (13.9 g, 44 mmol, 61%) was prepared from 3-formylphenyl-4-methylbenzenesulfonate 2a (72 mmol) as a yellow solid. TLC;Rf=0.2 (30% EA/ heptane).1H NMR (CDCl₃, 400 MHz) δ = 7.90 (S,1H), 7.74 (d, J = 8 Hz, 2H) , 7.53 (d, J
= 8 Hz, 1H), 7.32 (m, 5H) , 6.94 (d, j=8 Hz, 1H), 2.45 (s, 3H). 13C NMR (CDCl₃, 400 MHz) δ = 150.8, 150.1, 150.0, 145.6, 132.2, 130.3, 129.8, 129.4, 128.5, 122.9, 122.5, 122.3, 118.4, 21.7. HRMS calculated for C₁₆H₁₄O₄NS [M+H]⁺ 316.0643, found 316.0639.
TosMIC, DBU / DME Reflux 80 ⁰C, 2-3h
46
7.1.2.2 2-(Oxazol-5-yl)phenyl-4-methylbenzenesulfonate (3b)
2-(Oxazol-5-yl)phenyl-4-methylbenzenesulfonate 3b (2.3 g, 7.3 mmol, 40 %) was prepared from 2-formylphenyl-4-methylbenzenesulfonate 2b (18 mmol) as a brown solid. TLC;Rf=0.2 (30% EA/heptane).1H NMR (CDCl₃, 400 MHz) δ = 7.82 (S, 1H), 7.65 (m, 1H) , 7.62 (d, J = 8 Hz, 2H), 7.43 (s, 1H), 7.36 (m, 1H) 7.31 (m, 2H), 7,20 (d, j = 8, 2H), 2.38 (s, 3H). 13C NMR (CDCl₃, 400 MHz) δ = 150.1, 146.3, 145.7, 145.6, 132.2, 129.5, 129.3, 128.3, 127.2, 127.0, 126.0 122.6, 121.5, 21.6. HRMS (ESI) m/z: [M+H]⁺ calculated for C₁₆H₁₄O₄NS 316.0643, found 316.0647.
7.1.3 Standard procedure for oxazole synthesis by TosMIC
Compound 2 and 1.1 eq. of TosMIC were dissolved in anhydrous methanol (8 mL per 1 g of 2). 1.1 eq. of k₂CO₃ was added and the mixture was refluxed for 16 hours. Water was added and the organic layer was separated, washed 3 times with brine solution, dried over MgSO₄, filtered and the solvent was evaporated. The crude was purified using column
chromatography to yield the corresponding oxazole derivatives.
7.1.3.1 5-(3-Methoxyphenyl)oxazole (3c)
5-(3-Methoxyphenyl)oxazole 3c (2.26 g, 13 mmol, 44 %) was prepared from 3-methoxybenzaldehyde 2c (29 mmol) as a brown solid. TLC; Rf =0.34 (35% EA/heptane). 1H NMR (CDCl₃, 400 MHz δ = 7.89 (S, 1H), 7.33 (s, 1H), 7.31 (d, J = 8 Hz, 1H), 7.23 (d, J = 8 Hz, 1H), 7.17 (t, J = 2.6 Hz, 1H) , 6.87 (dd, j = 2.6, 8 Hz, 1H), 3.84 (s, 3H). 13C NMR (CDCl₃, 400 MHz δ = 159.9, 151.3, 150.3, 130.0, 128.9, 121.7, 116.8, 114.2, 109.7, 55.2. HRMS (ESI) m/z:
[M+H]⁺ calculated for C₁₀H₁₀O₂N 176.0711, found 176.704.
TosMIC, K₂CO₃ / Methanol Reflux 80 ⁰C, 16h
47
7.1.3.1 5-(2-Methoxyphenyl)oxazole (3d)
5-(2-Methoxyphenyl)oxazole 3d (1 g, 5.7 mmol, 30 %) was prepared from 2-methoxybenzaldehyde 2d (19 mmol) as a brown oil. TLC; Rf =0.37 (35% EA/heptane).1H NMR (CDCl₃, 400 MHz) δ = 7.89 (S,1H), 7.78 (d, J = 8 Hz, 1H) , 7.56 (s, 1H), 7.30 (t, J = 8 Hz, 1H), 7.04 (t, J = 8 Hz, 1H) , 6.97 (d, j = 8 Hz, 1H), 3.95 (s, 3H). 13C NMR (CDCl₃, 400 MHz) δ = 155.6, 149.4, 147.9, 129.2, 126.0, 125.4, 120.7, 116.9, 110.8, 55.4. HRMS (ESI) m/z: [M+H]⁺
calculated for C₁₀H₁₀O₂N 176.0711, found 176.704.
7.1.4 General procedure for 2,4-iodination of the oxazole by lithiation
Compound 3 was dissolved in dry THF (1 mL per 1 mmol of 3) and cooled to -78 ⁰C. 3 eq. of freshly prepared LiHMDS (1 M in THF) were added dropwise to the solution followed by stirring for 30 minutes. 3 eq. of Iodine were dissolved in dry THF (2 mL per 1 g Iodine) and added slowly to the reaction mixture at -78 ⁰C. The mixture was stirred for 1 hour and then left to be heated to rt. After that it was quenched with 10 % Na₂S₂O₃ solution and extracted with EA. The organic layer was separated, washed 3 times with brine solution, dried over MgSO₄, filtered and the solvent evaporated. The crude was purified by column
chromatography using EA/pentane as eluent in an appropriate ratio to yield the corresponding iodinated derivatives.
I₂(3 eq.), -78 ⁰C , 1h
LiHMDS(3 eq.)/THF, -78 ⁰C, 30 min
48
7.1.4.1 3-(2,4-Diiodooxazol-5-yl)phenyl-4-methylbenzenesulfonate (4a)
3-(2,4-Diiodooxazol-5-yl)phenyl-4-methylbenzenesulfonate 4a (3.46 g, 6.1 mmol, 62%) was prepared from 3-(oxazol-5-yl)phenyl 4-methylbenzenesulfonate 3a (9.84 mmol) as a yellow solid. TLC; Rf =0.22 (30% EA/heptane). 1H NMR (CDCl₃, 400 MHz) δ = 7.82 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 8 Hz, 2H), 7.54 (s, 1H), 7.40 (t, J = 8 Hz, 1H), 7.34 (d, J = 8 Hz, 2H), 7.06 (d, j = 8 Hz, 1H), 2.46 (s, 3H). 13C NMR (CDCl₃, 400 MHz) δ = 155.4, 149.7, 145.6, 132.2, 130.1, 129.9, 128.6, 127.7, 124.3, 123.5, 119.7, 101.5, 80.3, 21.8. HRMS (ESI) m/z: [M+K]⁺ calculated for C₁₆H₁₁O₄NI₂KS 605.8135, found 605.8129.
7.1.4.2 (2,4-Diiodooxazol-5-yl)phenyl-4-methylbenzenesulfonate 4b and 2-(2-iodooxazol-5-yl)phenyl-4-methylbenzenesulfonate (5b)
A mixture (2.7 g) of 2-(2,4-diiodooxazol-5-yl)phenyl-4-methylbenzenesulfonate 4b (1 g, 1.7 mmol, 23%) and 2-(2-iodooxazol-5-yl)phenyl-4-methylbenzenesulfonate 5b (1.7 g, 4 mmol, 50%) was prepared as a pale yellow solid from
2-(oxazol-5-yl)phenyl-4-methylbenzenesulfonate 3b (8 mmol). TLC;Rf=0.44 (30% EA/pentane).
7.1.5 General procedure for 2-iodination of the oxazole by lithiation
1 eq. of 3 was dissolved in dry THF (1 mL per 1 mmol of 3) and cooled to -78 ⁰C. 3 eq. of freshly prepared LiHMDS (1 M in THF) were added dropwise to the solution followed by stirring for 30 minutes. 1.2 eq. of Iodine were dissolved in dry THF (2 mL per 1 g Iodine) and added slowly to the reaction mixture at -40 ⁰C. The mixture was stirred for 1 hour and then left to be heated to rt. After that it was quenched with 10 % Na₂S₂O₃ solution and extracted with EA. the organic layer was separated, washed 3 times with brine solution, dried over MgSO₄, filtered and the
LiHMDS(3 eq.)/THF, -78 ⁰C, 30 min I₂(1.2 eq.), -40 ⁰C , 1h
49
solvent evaporated. The crude was purified by column chromatography using EA/pentane as eluent in an appropriate ratio to yield the corresponding iodinated derivatives.
7.1.5.1 2,4-Diiodo-5-(3-methoxyphenyl)oxazole (4c)
2,4-Diiodo-(3-methoxyphenyl)oxazole 4c (376 mg, 0.86 mmol, 30 %) was prepared from 5-(3-methoxyphenyl)oxazole 3c (2.8 mmol) as a yellowish crystalline solid. TLC; Rf =0.56 (35%
EA/heptane).1H NMR (CDCl₃, 400 MHz) δ = 7.50 (d, j=8 Hz, 1H), 7.45 (s, 1H), 7.37 (t, J = 8 Hz, 1H), 6.96 (d, j = 8 Hz, 1H), 3.87 (s, 3H). 13C NMR (CDCl₃, 400 MHz) δ = 159.6, 156.9, 129.9, 127.3, 118.4, 115.6, 111.2, 100.8, 79.5, 55.4. HRMS (ESI) m/z: [M+K]⁺ calculated for C₁₀H₇O₂NI₂K 465.8203, found 465.8190.
7.1.5.2 2-Iodo-5-(2-methoxyphenyl)oxazole (5d)
2-Iodo-methoxyphenyl)oxazole 4h (350 mg, 1.16 mmol, 81%) was prepared from 5-(2-methoxyphenyl)oxazole 3d (1.4 mmol) as a yellowish crystalline solid. TLC;Rf=0.42 (35%
EA/heptane). 1H NMR (CDCl₃, 400 MHz) δ = 7.73 (d, j=8 Hz, 1H), 7.46 (s, 1H), 7.31 (t, J = 8 Hz, 1H), 7.04 (t, J = 8 Hz, 1H), 6.97 (d, j = 8 Hz, 1H), 3.95 (s, 3H). 13C NMR (CDCl₃, 400 MHz) δ = 155.3, 154.2, 129.6, 129.2, 126.0, 120.8, 116.1, 110.8, 99.1, 55.4. HRMS (ESI) m/z: [M+K]⁺
calculated for C₁₀H₈O₂NIK 339.9236, found 339.9230.
7.1.6 General procedure for TMPMgCl•LiCl based oxazole synthesis
Compound 3 was dissolved in dry THF and cooled to -40 ⁰C approximately. Two equivalents of TMPMgCl•LiCl were added and the mixture stirred for 30 minutes before addition of three equivalents of 0.5 M LiCl solition in THF followed by dropwise addition of the iodine in appropriate eq., dissolved in THF (2 mL THF per 1 g iodine).
TMPMgCl•LiCl (2 eq.)/THF, - 40 ⁰C , 30 min
0.5 M LiCl (3 eq.), I₂ / THF, - 13 ⁰C, 1h
50
7.1.7 General procedure for the Suzuki coupling on the oxazole
compound 4 was dissolved in degassed dioxane. Then 1.4 eq. of N-Boc-2-pyrroleboronic acid, 3 eq. of Cesium carbonate and degassed water were added, respectively. 0.1 eq. of the catalyst, PdCl₂(dppf).CH₂Cl₂ was last added and the mixture was degassed again and heated with stirring on oil bath for 2-5 hours at 50 ⁰C. Water and EA were then added and the organic layer separated, washed 3 times with brine solution, dried over MgSO₄, filtered and the solvent was evaporated. Column chromatography was carried to purify the crude using EA/pentane in an appropriate ratio to give the corresponding product.
7.1.7.1 tert-butyl-2-(4-iodo-5-(3-(tosyloxy)phenyl)oxazol-2-yl)-1H-pyrrole-1-carboxylate (6a)
tert-butyl-2-(4-iodo-5-(3-(tosyloxy)phenyl)oxazol-2-yl)-1H-pyrrole-1-carboxylate 6a (280 mg, 0.46 mmol, 60 %) was prepared from
3-(2,4-diiodooxazol-5-yl)phenyl-4-methylbenzenesulfonate 4a ( 0.76 mmol) as a yellowish oil. TLC; Rf =0.37 (30% EA/heptane).
1H NMR (CDCl₃, 400 MHz) δ = 7.89 (d, J = 8 Hz, 1H), 7.74 (d, J = 8 Hz, 2H), 7.63 (s, 1H), 7.45 (m, 1H), 7.39 (t, J = 8 Hz, 1H), 7.32 (d, J = 8 Hz, 2H), 7.04 (d, j = 8 Hz, 1H), 6.76 (q, J = 2.6 Hz, 1H), 6.30 (t, J = 4 Hz, 1H), 2.42 (s, 3H), 1.45 (s, 9H). 13C NMR (CDCl₃, 400 MHz) δ = 155.7, 150.1, 149.8, 148.2, 145.6, 132.3, 130.3, 129.8, 129.6, 128.5, 124.7, 123.6, 122.5, 122.1, 120.6, 119.0, 118.1, 111.0, 84.6, 27.7, 21.7.
PdCl₂(dppf).CH₂Cl₂ , Dioxan/Water N-Boc-2-pyrroleboronic, Cs₂Co₃, 50 ⁰C, 2-5h
51
7.1.7.2 tert-butyl-2-(4-iodo-5-(2-(tosyloxy)phenyl)oxazol-2-yl)-1H-pyrrole-1-carboxylate (6b)
tert-butyl-2-(4-iodo-5-(2-(tosyloxy)phenyl)oxazol-2-yl)-1H-pyrrole-1-carboxylate 6b (230 mg, 0.4 mmol, 58 %)) was prepared from
2-(2,4-diiodooxazol-5-yl)phenyl-4-methylbenzenesulfonate 4b (0.65 mmol). TLC; Rf=0.38 (35% EA/heptane). 1H NMR (CDCl₃, 400 MHz) δ = 7.61 (d, J = 8 Hz, 1H), 7.56 (d, J = 8 Hz, 1H), 7.48 (t, J = 8 Hz, 1H), 7.42 (d, J = 8 Hz, 3H), 7.35 (t, J = 8 Hz, 1H), 7.09 (d, j = 8 Hz, 2H), 6.77 (q, J = 2 Hz, 1H), 6.31 (t, J = 4 Hz, 1H), 2.32 (s, 3H), 1.44 (s, 9H). 13C NMR (CDCl₃, 400 MHz) δ = 156.7, 148.0, 147.4, 146.4, 145.4, 131.9, 131.0, 130.7, 129.7, 127.9, 127.0, 125.3, 124.5, 121.0, 119.8, 119.3, 111.0, 85.0, 83.0, 27.6, 21.7. HRMS (ESI) m/z: [M+K]⁺ calculated for C₂₅H₂₃O₆N₂IKS 644.9958, found 644.9953.
7.1.7.3 tert-butyl 2-(5-(2-(tosyloxy)phenyl)oxazol-2-yl)-1H-pyrrole-1-carboxylate (7b)
tert-butyl-2-(5-(2-(tosyloxy)phenyl)oxazol-2-yl)-1H-pyrrole-1-carboxylate 7b (75 mg, 0.15 mmol) was prepared from a 1 g mixture of
2-(2,4-diiodooxazol-5-yl)phenyl-4-methylbenzenesulfonate 4b and 2-(2-iodooxazol-5-yl)phenyl-4-2-(2,4-diiodooxazol-5-yl)phenyl-4-methylbenzenesulfonate 5b.
TLC;Rf=0.33 (35% EA/heptane). 1H NMR (CDCl₃, 400 MHz) δ = 7.68 (m, 3H), 7.49 (s, 1H), 7.43 (m, 1H), 7.40 (m, 1H), 7.30 (m, 2H), 7.23 (d, j = 8 Hz, 2H), 6.70 (q, J = 2 Hz, 1H), 6.28 (t, J = 4 Hz, 1H), 2.37 (s, 3H), 1.40 (s, 9H). 13C NMR (CDCl₃, 400 MHz) δ = 155.0, 148.2, 146.1, 145.6, 145.5, 132.5, 129.7, 129.0, 128.4, 127.4, 127.1, 126.6, 124.7, 122.5, 121.7, 120.7, 119.0, 111.0, 84.6, 27.6, 21.7. HRMS (ESI) m/z: [M+K]⁺ calculated for C₂₅H₂₄O₆N₂KS 519.0992, found 519.0986
52
7.1.8 Boc group de-protection
6a or 7b was dissolved in DCM (5 mL per 1 g of 6a) and cooled to 0 ⁰C. TFA (5 mL per 1 g of 6a) was added dropwise then 50 microliters of water were added and the reaction mixture was stirred for 16 hours. The mixture was quenched with aqueous solution of NHCO₃. The organic layer was separated and washed 3 times with brine solution, dried over MgSO₄, filtered and the solvent evaporated. Column chromatography was carried to purify the crude using EA/pentane in appropriate ratio to yield the corresponding product.
7.1.8.1 3-(4-Iodo-2-(1H-pyrrol-2-yl)oxazol-5-yl)phenyl-4-methylbenzenesulfonate (8a)
3-(4-Iodo-2-(1H-pyrrol-2-yl)oxazol-5-yl)phenyl-4-methylbenzenesulfonate 8a (198 mg, 0.4 mmol, 67.7 %) was prepared from tert-butyl-2-(4-iodo-5-(3-(tosyloxy)phenyl)oxazol-2-yl)-1H-pyrrole-1-carboxylate 6a (0.57 mmol). TLC; Rf =0.45 (30% EA/heptane). 1H NMR (CDCl₃, 400 MHz) δ = 9.17 (s, 1H), 7.90 (d, J = 8 Hz, 1H), 7.76 (d, J = 8 Hz, 2H), 7.60 (s, 1H), 7.39 (t, J = 8 Hz, 1H), 7.34 (d, J = 8 Hz, 2H), 7.03 (d, j = 8 Hz, 1H), 6.98 (s, 1H), 6.88 (s, 1H), 2.45 (s, 3H). 13C NMR (CDCl₃, 400 MHz) δ = 157.3, 149.8, 146.8, 145.6, 137.1, 132.3, 130.0, 129.9, 128.8, 128.6, 124.0, 122.5, 122.2, 119.4, 119.0, 111.6, 110.8, 21.8. HRMS (ESI) m/z: [M+K]⁺
calculated for C₂₀H₁₅O₄N₂IKS 544.9434, found 544.9426.
TFA/DCM,0 ⁰C- rt , 16 h
53
7.1.8.2 2-(2-(1H-pyrrol-2-yl)oxazol-5-yl)phenyl 4-methylbenzenesulfonate (9b)
2-(2-(1H-pyrrol-2-yl)oxazol-5-yl)phenyl 4-methylbenzenesulfonate 9b (40 mg, 0.1 mmol, 67%) was prepared as a grey solid from 7b (75 mg, 0.15 mmol) TLC; Rf =0.44 (3%
EA/heptane). 1H NMR (DMSO-d6, 400 MHz) δ = 11.96 (s, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.67 (d, J = 7.6 Hz, 2H), 7.42 (m, 5H), 7.23 (d, j = 7.6 Hz, 1H), 7.04 (s, 1H), 6.79 (s, 1H), 6.24 (s, 1H), 2.31 (s, 3H). 13C NMR (DMSO-d6, 400 MHz) δ = 156.7, 146.8, 145.3, 144.4, 132.1, 130.7, 130.0, 128.8, 128.5, 127.8, 127.5, 123.3, 123.0, 122.1, 119.9, 111.4, 110.4, 21.8. HRMS (ESI) m/z: [M+K]⁺ calculated for C₂₀H₁₆O₄N₂KS 419.0467, found 419.0456.
7.1.9 De-iodination
3-(4-Iodo-2-(1H-pyrrol-2-yl)oxazol-5-yl)phenyl-4-methylbenzenesulfonate 8a (0.1 mmol) was dissolved in 4.5 mL of EtOH. 0.25 mL HCL and 10 eq. of Zn were added, respectively. The mixture was heated at reflux for 30 minutes. Water and acetone were added and the product crystallized out of the solution.
3-(2-(1H-pyrrol-2-yl)oxazol-5-yl)phenyl-4-methylbenzenesulfonate 9a (20 mg, 0.05 mmol, 53 %) was obtained as a grey solid. TLC; Rf
=0.12 (30% EA/heptane). 1H NMR (CDCl₃, 400 MHz) δ = 9.55 (s, 1H), 7.76 (d, J = 8 Hz, 2H), 7.54 (d, J = 8 Hz, 1H), 7.35 (m, 3H), 7.28 (d, j = 7.6 Hz, 2H), 7.01 (s, 1H), 6.93 (d, J = 8 Hz, H), 6.25 (s, 1H), 2.46 (s, 3H). 13C NMR (CDCl₃, 400 MHz) δ = 156.7, 148.4, 145.6, 144.4, 132.3, 130.2, 129.8, 129.6, 128.6, 123.5, 122.4, 121.8, 120.1, 117.9, 110.8, 110.6, 100.0, 21.7.
HRMS (ESI) m/z: [M+H]⁺ calculated for C₂₀H₁₅O₄N₂S 379.0752, found 379.0751.
HCl, Zn(10 equ.), EtOH, Reflux, 30 min
54
7.1.10 De-tosylation
3-(4-Iodo-2-(1H-pyrrol-2-yl)oxazol-5-yl)phenyl-4-methylbenzenesulfonate 8a (0.1 mmol) was dissolved in 4.5 mL of EtOH. 0.5 mL 20% NaOH solution was added. The mixture was stirred for 10 minutes at 70 ⁰C. Water and Ethyl acetate were added and the organic layer was separated and washed 2 times with 20 mL brine solution, dried over MgSO₄, filtered and the solvent evaporated. 3-(4-iodo-2-(1H-pyrrol-2-yl)oxazol-5-yl)phenol 10a (32 mg, 0.09 mmol, 92%) was obtained as a grey solid. TLC; Rf =0.37 (30% EA/pentane). 1H NMR (acetone-d6, 400 MHz) δ = 11.12 (s, 1H), 8.69 (s, 1H), 7.54 (d, J = 8 Hz, 2H), 7.35 (t, J = 8 Hz, 1H), 7.10 (s, 1H), 6.91 (d, j = 8 Hz, 1H), 6.88 (s, 1H), 6.29 (s, 1H). 13C NMR (acetone-d6, 400 MHz) δ = 158.6, 148.9, 130.9, 129.7, 123.5, 123.3, 120.2, 118.0, 116.8, 113.3, 112.0, 111.0, 80.7. HRMS (ESI) m/z: [M+H]⁺ calculated for C₁₃H₈O₂N₂I 350.9630, found 350.9633.
7.1.11 De-iodination and de-tosylation
8a or 8b was dissolved in EtOH (90 mL per 1 g of 8a or 8b). 20% NaOH solution (10 mL per 1 g of 8a or 8b) was added. The mixture was stirred and 10 eq. of Zn was added and the mixture was stirred at reflux for 5 hours.
20 % NaOH, EtOH, 70 ⁰C, 10 min
20 % NaOH, Zn(10 eq),EtOH, Reflux , 5h
55
7.1.11.1 3-(2-(1H-pyrrol-2-yl)oxazol-5-yl)phenol (11a)
3-(2-(1H-pyrrol-2-yl)oxazol-5-yl)phenol 11a (10 mg, 0.04 mmol, 40 %) was prepared as a grey solid from 3-(4-iodo-2-(1H-pyrrol-2-yl)oxazol-5-yl)phenyl-4-methylbenzenesulfonate 8a (0.1 mmol, 50 mg) TLC;Rf=0.15 (30% EA/pentane). 1H NMR (DMSO-d6, 400 MHz) δ = 11.92 (s, 1H), 9.65 (s, 1H), 7.62 (s, 1H), 7.26 (t, J = 7.8 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.15 (s, 1H), 7.00 (s, 1H), 6.76 (d, J = 7.6 Hz, 2H), 6.22 (s, 1H). HRMS (ESI) m/z: [M+H]⁺ calculated for C₁₃H₉O₂N₂ 225.0664, found 225.0669.
7.1.11.2 2-(2-(1H-pyrrol-2-yl)oxazol-5-yl)phenol (11b)
2-(2-(1H-pyrrol-2-yl)oxazol-5-yl)phenol 11b (80 mg, 0.3 mmol) was prepared as a dark grey solid from a crude mixture of 8b and 9b. TLC;Rf=0.25 (35% EA/pentane).1H NMR (DMSO-d6, 400 MHz) δ = 11.91 (s, 1H), 10.38 (s, 1H), 7.78 (d, J = 8 Hz, 1H), 7.52 (s, 1H), 7.17 (t, J = 8 Hz, 1H), 6.96 (m, 3H), 6.78 (s, 1H), 6.22 (q, j = 2 Hz, 1H). 13C NMR (DMSO-d6, 400 MHz) δ = 155.4, 154.3, 146.7, 129.3, 126.6, 125.7, 122.7, 120.4, 120.0, 116.4, 115.7, 110.6, 110.2.
HRMS (ESI) m/z: [M+H]⁺ calculated for C₁₃H₉O₂N₂ 225.0664, found 225.0670.
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