Preparation of 2-aminobenzyl-triphenylphosphonium bromide (23) from 2- aminobenzyl alcohol (22)

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4.2.1.2. Preparation of [2-(ethoxycarbonylacetamido)benzyl] triphenylphosphonium bromide (24) by N-acylation of (23)

To the white suspension of 4.9 g (1 eq., 10.9 mmol, 448.335 g mol^-1) 2-aminobenzyl- triphenylphosphonium bromide (23) in DCM (25 mL), 2.4 mL (1.7 eq., 18.5 mmol, 150.56 g mol^-1) ethyl malonyl chloride was added at ambient temperature. The reaction mixture was stirred at rt for 1 hour, when TLC showed full conversion (DCM:MeOH:sat. NH4OH = 90:10:1; Rf (23) = 0.48; Rf (24) = 0.6). The reaction mixture was evaporated in vacuo. The residue was washed with EtOH and Et₂O, and dried in an exsiccator in the presence of P₂O₅ to obtain 5.1 g (84%) 24 as a beige solid.

1H NMR (399.8 MHz, DMSO-d₆, 25 °C) δ = 1.18 (t, J = 7.1; 3H, CH₃-14); 3.22 (s, 2H; CH₂-11); 4.08 (q, J = 7.1;

2H, CH₂-13); 5.26 (d, ²J_PH = 15.3; 2H, CH₂-7); 6.96 (dt, J = 8.0; J = 2.0; 1H, CH-6); 7.01 (t, J = 7.3; 1H, CH-5); 7.28–

7.35 (m, 1H, CH-4); 7.50 (d, J = 8.1; 1H, CH-3); 7.63 (dd,

3JPH = 12.6; J = 8.0; 6H, 6× CH-2’); 7.72 (td, ⁴JPH = 8.0; J = 3.5; 6H, 6× CH-3’); 7.89 (t, J = 8.0; 3H, 3× CH-4’); 9.78 (brs, 1H, NH-9) ppm. ¹³C NMR (100.5 MHz, DMSO-d6, 25 °C): δ = 13.9 (CH3-14); 25.0 (d,

1JPC = 47.6; CH2-7); 42.6 (CH2-11); 60.6 (CH2-13); 117.6 (d, ¹JPC= 85.4; 3× C-1’); 120.8 (d,

2JPC = 7.8; C-1); 125.31 (d, ⁴JPC = 10.0; CH-3); 125.34 (d, ⁴JPC = 10.0; CH-5); 128.9 (d, ⁵JPC = 3.7; CH-4); 130.0 (d, ³JPC = 12.5; 6x CH-3’); 131.4 (d, ³JPC = 5.1; CH-6); 133.8 (d, ²JPC = 10.0; 6× CH-2’); 135.0 (d, ⁴JPC = 2.8; 3× CH-4’); 137.2 (d, ³JPC = 6.1; C-2); 164.0 (C-10);

167.5 (C-12) ppm. HRMS: calcd for C30H29NP [M+H]⁺: 482.18796; found: 482.18752;

delta = -0.9 ppm. Mp.: 234–238 ºC (Lit.: 236 °C^[27]).

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4.2.1.2.1. Preparation of 21 by intramolecular Wittig-reaction from 24 with NaH as the base

To a yellow solution of 0.5 g (1.0 eq., 0.9 mmol, 562.445 g mol^-1) 24 in DCM (5 mL), 40 mg (1.1 eq. 1.1 mmol, 24 g mol^-1) sodium hydride (60 wt% in mineral oil) was added at ambient temperature. The reaction mixture was stirred for 3 hours, and then water (10 mL) was added. The layers were separated and the aqueous layer was extracted with DCM (10 mL) twice. The combined organic phases were washed with brine, dried over anhydrous Na₂SO₄ and evaporated in vacuo. The green sticky crude product was purified by column chromatography eluting with n-hexane:ethyl acetate = 4:1 isocratic elution to obtain 0.12 g (61%) ethyl 2-[(2-methylphenyl)carbamoyl]acetate (21a) as white crystals. Indole 21 was not formed in the reaction.

1H NMR (399.8 MHz, CDCl₃, 25 °C) δ = 1.33 (t, J = 7.2;

3H, CH₃-6); 2.32 (s, 3H, CH₃-7’); 3.50 (s, 2H, CH₂-2); 4.27 (q, J = 7.2; 2H, CH₂-5); 7.06 (td, J = 7.5; J = 1.0; 1H; CH- 4’); 7.16–7.24 (m, 2H, CH-3’, CH-5’); 7.96 (d, J = 8.1; 1H, CH-6’); 9.26 (br s, 1H, NH-4) ppm. ¹³C NMR (100.5 MHz, CDCl₃, 25 °C): δ 14.1 (CH₃-6);

17.8 (CH3-7’); 41.3 (CH2-2); 61.9 (CH2-5); 122.2 (CH-6’); 124.9 (CH-4’); 126.7 (CH-3’);

128.5 (C-2’); 130.4 (CH-5’); 135.7 (C-1’); 162.9 (C-3); 170.4 (C-1) ppm. HRMS: calcd for C12H16O3N [M+H]⁺: 222.11247; found: 222.11249; delta = 0.1 ppm. Mp.: 77–78 ºC (Lit.: 76- 77 °C^[313]).

4.2.1.2.2. Preparation of 21 by intramolecular Wittig-reaction from 24 with lithium bis(trimethylsilyl)amide as the base

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To a three-necked round bottom flask, which was equipped with a septum, a Dean- Stark apparatus and a drying tube filled with CaCl₂, a suspension of 20.0 g (1 eq., 35.6 mmol, 562.445 g mol^-1) 24 in toluene (300 mL), which was dried overnight on 3Å molecular sieve, was added. The suspension was refluxed for 30 min in order to remove the traces of water and then it was cooled to 60 °C. Then 36 mL (1 eq., 0.36 mol, 1 M) lithium bis(trimethylsilyl)amide solution in THF was added to the suspension and the reaction mixture was stirred for 15 min, when TLC showed full conversion (DCM:acetone = 9:1; Rf

(24) = 0.95; Rf (21) = 0.36). The reaction mixture was cooled to rt, then it was filtered. The mother liquor was treated with Et2O, and the precipitated triphenylphospine oxide was filtered again. The filtrate was evaporated in vacuo, and the crude product was purified by flash column chromatography eluting with 0-20% gradient of EtOAc in n-hexane, then isocratic elution to obtain 4.3 g (60%) 21 as a light yellow oil.

4.2.1.3. Preparation of ethyl 2-[1-(2-bromoethyl)-2,3-dihydro-1H-indol-2-yl]acetate (6) by reductive N-alkylation reaction of ethyl 2-(2,3-dihydro-1H-indol-2- yl)acetate (5) with bromoacetic acid

To solution of bromoacetic acid (10.15 g, 73 mmol, 138.95 g mol^-1, 15.2 eq.) in THF (10 mL), which was cooled to 0 ºC with ice bath, sodium [tetrahydrido-borate(III)] (1.0 g, 26.4 mmol, 5.5 eq., 37.83 g mol^-1) was added (slightly exothermic reaction, while gas generates). The white suspension was stirred at 0 ºC until the gas generation stopped, then a dark brownish solution of ethyl 2-(2,3-dihydro-1H-indol-2-yl)acetate (5) (1.0 g, 4.8 mmol, 205.233 g mol^-1, 1.0 eq.) in THF (10 mL) was added. After the argon inlet was discharged, the caramel coloured reaction mixture was equipped with a reflux condenser and it was stirred at reflux temperature for 3 hours, when the TLC showed full conversion (n-hexane:EtOAc = 4:1; R_f (5) = 0.36; R_f (6) = 0.50). To the reaction mixture ethanol (20 mL) was added, and it was cooled to room temperature. The white precipitate was removed by filtration. The mother liquor was evaporated in vacuo and the residue dissolved in DCM (100 mL), which was washed with the solution of 1 M NaOH solution (65 mL) and water (40 mL). The aqueous phase was extracted with DCM (100 mL) and the combined organic phase dried over

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anhydrous Na₂SO₄ and evaporated in vacuo resulting in 1.6 g dark brown oil (89.5% 6 in LC- DAD-MS). The crude reaction mixture was purified by column chromatography (ca. 160 g silica gel) eluting with n-hexane:EtOAc=10:1 isocratic elution to obtain 1.0 g (67%) ethyl 2- [1-(2-bromoethyl)-2,3-dihydro-1H-indol-2-yl]acetate (6).

4.2.1.4. Preparation of 1H,2H,3H,4H,5H,11H,11aH-[1,4]diazepino[1,7-a]indole (8) 4.2.1.4.1. Using 5 eq. of borane-dimethylsulfide complex

To a round-bottomed flask, which was equipped with a condenser and a drying tube filled with CaCl2, a light yellow solution of 1.0 g (1 eq., 5.0 mmol, 202.253 g mol^-1) diazepinone (7) in THF (60 mL) and 13 mL (5 eq., 25.0 mmol, 2 M in THF) borane-dimethyl sulphide complex were added under argon atmosphere. The reaction mixture was stirred at 65

°C for 12 h, when TLC showed full conversion (DCM:MeOH = 9:1; R_f (7) = 0.50; R_f (8) = 0.86). First, ethanol (36 mL) was added to quench the excess of reagent, then the reaction mixture was evaporated in vacuo. To the residue, which was redissolved in ethanol (50 mL), 1 M HCl solution (32 mL) was added and stirred at reflux temperature for 1 h. The cooled reaction mixture was first alkalified to pH>13 with 1 M NaOH solution (ca. 46 mL), then it was extracted with DCM (40 mL) three times. The combined organic solution was washed with brine, dried over Na2SO4 and evaporated in vacuo. The crude product was purified by flash column chromatography eluting with 0-5% gradient of MeOH in DCM, then isocratic elution to obtain 0.68 g (73%) 8 as s light yellow oil.

1H NMR (399.8 MHz, CDCl3, 25 °C) 1.83 (dddd, J = 16.6; J = 14.2;

J = 10.1; J = 4.3; 1H, CHa-1); 1.95 (ddd; J = 14.1; J = 6.7; J = 3.7;

1H; CHb-1); 2.26 (br s, 1H, NH-3); 2.67 (dd, J = 15.7; J = 9.1; 1H, CHa-11); 2.80 (ddd, J = 13.6; J = 10.5; J =3.6; 1H, CHa-2); 2.91–3.05 (m, 2H, CHa-4, CHa-5); 3.06–3.28 (m, 3H, CHb-2, CHb-4, CHb-11); 3.53 (ddd, J = 13.1; J = 7.8; J = 2.9; 1H, CHb-5); 3.89 (qd, J = 9.3; J = 2.5; 1H, CH-11a); 6.35 (d, J = 7.8; 1H, CH-7);

6.60 (dd, J = 7.1; J = 7.6; 1H, CH-9); 7.01 (d, J = 7.1; 1H, CH-10); 7.06 (d, J = 7.6; 1H, H-8) ppm. ¹³C NMR (100.5 MHz, CDCl₃, 25 °C) δ 37.0 (CH₂-11); 39.3 (CH₂-1); 47.8 (CH₂-4);

48.0 (CH₂-2); 50.7 (CH₂-5); 64.1 (CH-11a); 106.1 (CH-7); 117.0 (CH-9); 123.8 (CH-10);

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127.4 (CH-8); 128.6 (CH-10a); 152.7 (CH-7a) ppm. HRMS: calcd for C₁₂H₁₇N₂ [M+H]⁺: 189.13863; found: 189.13849; delta = -0.7 ppm.

4.2.1.4.2. Using 3 eq. of borane-dimethylsulfide complex

To a round bottom flask, which was equipped with a condenser and a drying tube filled with CaCl2, a light yellow solution of 0.5 g (1 eq., 2.5 mmol, 202.253 g mol^-1) diazepinone (7) in THF (15 mL) and 0.75 mL (3 eq., 7.5 mmol, 10 M in THF) borane-dimethyl sulphide complex were added under argon atmosphere. The reaction mixture was refluxed for 16 hours, when TLC showed full conversion (DCM:MeOH = 9:1; Rf (7) = 0.5; Rf (8) = 0.86).

First, ethanol (31 mL) was added to quench the excess of reagent,then the reaction mixture was evaporated in vacuo. To the residue, which was redissolved in ethanol (15 mL), 2 M HCl solution (11 mL) was added and stirred at reflux temperature for an hour. The cooled reaction mixture was first alkalified to pH>13 with 2 M NaOH solution (ca. 16 mL), then it was extracted with DCM (30 mL) twice. The combined organic solution was washed with brine, dried over Na2SO4 and evaporated in vacuo to obtain 0.68 g (73%) 8 as a light yellow oil. LC- DAD-MS: >98.5%.

4.2.1.5. Preparation of tert-buthyl

1H,2H,3H,4H,5H,11H,11aH-[1,4]diazepino[1,7-a]indole-3-carboxylate (4) 4.2.1.5.1. Preparation of 4 from compound 8

To a light yellow solution of 1.37 g (1 eq., 7.3 mmol, 188.289 g mol^-1) 8 and 1.55 mL (1.5 eq., 11 mmol, 101.19 g mol^-1, 0.726 g mL^-1) TEA in DCM (65 mL), which was cooled to 0 °C under argon atmosphere, a solution of 1.91 g (1.2 eq., 8.7 mmol, 218.25 g mol^-1) di-tert- butyl dicarbonate in DCM (10 mL) was added. After removing the cooling bath, the reaction mixture was stirred at ambient temperature for 2 hours, when TLC showed full conversion (DCM:MeOH:sat. NH₄OH = 90:10:1; R_f (8) = 0.5; R_f (4) = 0.93). Saturated NaHCO₃ solution (28 mL) and water (28 mL) were added to quench the excess of reagent, and then the reaction mixture was separated. The aqueous phase was extracted with DCM (40 mL) three times. The combined organic solution was washed with brine (40 mL), dried over Na₂SO₄ and

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evaporated in vacuo. The crude product was purified by flash column chromatography eluting 10% of EtOAc in n-hexane isocratic elution to obtain 2.01 g (96%) 4 as a white solid.

Owing to the hindered rotation at the carbamoyl moiety, most signals in the ¹³C spectrum and some signals in the ¹H spectrum are duplicated, which is indicated by slash mark (/) in the following peak lists.

1H NMR (799.9 MHz, DMSO-d6, 30 °C) δ 1.39 (s, 9H, 3×

CH3-14); 1.74 (m, 1H, CHa-1); 1.94/1.98 (m, 1H, CHb-1);

2.57 (dd, J = 15.6; J = 9.6; 1H, CHa-11); 2.78 (m, 1H, CHa- 5); 3.15 (dd, J = 15.6; J = 9.0; 1H, CHb-11); 3.27/3.29 (m, 1H, CHa-2); 3.49 (m, 1H, CHa-4); 3.54–3.62 (m, 3H, CHb-2, CHb-4, CH-11a); 3.65 (m, 1H, CHb-5); 6.44 (br d, J = 8.4; 1H, CH-7); 6.55 (t, J = 7.3; 1H, CH-9); 6.95-6.99 (m, 2H, CH-8, CH-10) ppm. ¹³C NMR (201.1 MHz, DMSO-d6, 30 °C) δ 28.0 (3× CH3-14); 35.2/35.5 (CH2-1); 35.9/36.0 (CH2-11); 44.3/44.9 (CH2-2); 45.2/45.7 (CH2-4); 47.3 (CH2-5); 64.0/64.6 (CH-11a); 78.5 (C-13); 106.7/106.7 (CH-7); 117.1 (CH-9);

123.7 (CH-10); 127.1 (CH-8); 128.2 (C-10a); 152.3/152.4 (C-7a); 154.3 (C-12) ppm. HRMS:

calcd for C17H25O2N2 [M+H]⁺: 289.19105; found: 289.19083; delta = -0.78 ppm. Mp.:

74-77 ºC (Lit.: N.A.). LC-DAD-MS > 97%.

4.2.1.5.2. Preparation of 4 from compound 7 using telescoped synthesis

To a light yellow suspension of 0.5 g (1 eq., 2.5 mmol, 202.253 g mol^-1) diazepinone (7) in abs. THF (5 mL), 3.7 mL (3 eq., 7.5 mmol, 2 M in THF) borane-dimethyl sulphide complex was added under argon atmosphere. The reaction mixture was refluxed for 18 h, when TLC showed full conversion (DCM:MeOH = 9:1; Rf (7) = 0.5; Rf (8) = 0.86). First, ethanol (1.5 mL) was added to quench the excess of reagent, then the reaction mixture was evaporated in vacuo. To the residue, which was redissolved in 1,4-dioxane (4 mL), 6 M HCl solution (2 mL) was added and stirred at reflux temperature for 1 h. The reaction mixture was first cooled to 0 °C and alkalified to pH>9 with 2 M NaOH solution (ca. 4.5 mL). Then the solution of 0.59 g (1.1 eq., 2.7 mmol, 218.25 g mol^-1) di-tert-butyl dicarbonate in 1,4-dioxane (1.4 mL) was added to the reaction mixture, which was stirred at ambient temperature for 30

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min, when TLC showed full conversion (DCM:MeOH:sat. NH₄OH = 90:10:1; R_f (8) = 0.5; R_f (4) = 0.93). Distilled water (10 mL) was added to dissolve the precipitate, and the mixture was extracted with ethyl acetate (30 mL) three times. The combined organic solution was washed with brine, dried over Na2SO4 and evaporated in vacuo to obtain 0.68 g (95%) 4 as a light yellow solid. LC-DAD-MS > 95%.

4.2.1.6. Preparation of 9-bromo tert-butyl 1H,2H,3H,4H,5H,11H,11aH- [1,4]diazepino[1,7-a]indole-3-carboxylate (3)

To a solution of 2.0 g (1 eq., 6.9 mmol, 288.385 g mol^-1) 4 in acetonitrile (100 mL), 1.36 g (1.1 eq., 7.6 mmol, 177.98 g mol^-1) NBS was added. The reaction mixture was stirred at rt for 3 h, when TLC showed full conversion (n-hexane:EtOAc = 4:1; Rf (4) = 0.53; Rf (3) = 0.43). The crude product was purified by column chromatography eluting 20% of acetone in cyclohexane isocratic elution to obtain 1.58 g (62%) 3 as a white solid and 0.35 g (14%) 3a as a light yellow oil.

Owing to the hindered rotation at the carbamoyl moiety, most signals in the ¹³C spectrum are duplicated, which is indicated by slash mark (/) in the following peak lists.

1H NMR (3) (499.9 MHz, DMSO-d6, 25 °C) δ 1.38 (s, 9H, 3× CH₃-14); 1.67-1.77 (m, 1H, CH_a-1); 1.87-1.98 (br m, 1H, CHb-1); 2.58 (dd, J = 16.2; J = 9.1; 1H, CHa-11);

2.75-2.86 (m, 1H, CH_a-5); 3.17 (dd, J = 16.2; J = 9.1; 1H, CH_b-11); 3.19-3.30 (m, 1H, CH_a-2); 3.41-3.50 (m, 1H, CH_a-4); 3.54-3.74 (m, 4H, CH_b-2, CH_b-4, CH_b-5, CH-11a); 6.39 (d, J = 8.9; 1H, CH-7); 7.08- 7.13 (m, 2H, CH-8, CH-10) ppm. ¹³C NMR (3) (125.7 MHz, DMSO-d₆, 25 °C) δ 28.0 (3×

CH₃-14); 35.2/35.5 (CH₂-1); 35.5/35.6 (CH-11a); 44.3/44.9 (CH₂-2); 44.9/45.4 (CH₂-4); 46.9 (CH₂-5); 63.9/64.5 (CH-11a); 78.5 (C-13); 107.61/107.63 (C-9); 107.9/108.0 (CH-7); 126.4 (CH-10); 129.5 (CH-8); 131.1 (C-10a); 151.47/151.51 (C-7a); 154.2 (C-12) ppm. HRMS (3):

calcd for C17H24O2N2Br [M+H]⁺: 367.10157; found: 367.10135; delta = -0.6 ppm. Mp.: 110- 111 ºC (Lit.: N.A.).

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9,11-Dibromo tert-butyl 1H,2H,3H,4H,5H,11H,11aH-[1,4]diazepino[1,7-a]indole-3- carboxylate (3a):

1H NMR (3a) (399.8 MHz, CDCl3, 25 °C) δ 1.47 (s, 9H, 3× CH₃); 1.63-1.83 (m, 1H, CH_a-1); 2.01-2.14 (m, 1H, CHb-1); 2.59 (dd, J = 16.5; J = 8.0; 1H, CHa-11); 2.74- 2.88 (m, 1H, CHa-5); 3.32 (dd, J = 16.5; J = 9.9; 1H, CHb- 11); 3.36-3.84 (m, 5H, CH2-2, CH2-4, CH-11a); 4.56-4.72 (m, 1H, CHb-5); 7.03 (br s, 1H, CH-10); 7.32 (br s, 1H, CH-8) ppm.

Due to the hindered rotation at the carbamoyl moiety, most signals in the ¹³C spectrum are duplicated, which is indicated by slash mark (/) in the peak list.

13C NMR (3a) (100.5 MHz, CDCl3, 25 °C) δ 28.5 (3× CH3-14); 35.7/35.9 (CH2-1); 36.0/36.1 (CH2-11); 44.4/44.9 (CH2-2); 48.4/48.6 (CH2-4); 50.0/50.6 (CH2-5); 66.4 (CH-11a); 79.6/79.7 (C-13); 102.6/103.3 (C-7); 110.0/110.1 (C-9); 126.4 (CH-10); 133.7/134.0 (C-10a); 134.5 (CH-8); 148.0/148.1 (C-7a); 155.4 (C-12) ppm. HRMS (3a): calcd for C17H23O2N2Br2

[M+H]⁺: 445.01208; found: 445.01197; delta = -0.25 ppm.

4.2.1.7. Preparation of 9-bromo tert-butyl

1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indole-3-carboxylate (2) 4.2.1.7.1. Preparation of 2 from compound 3

To a colourless solution of 0.34 g (1 eq., 0.9 mmol, 367.28 g mol^-1) 3 in THF (65 mL), which was cooled to 0 °C under argon atmosphere, solution of 0.23 g (1.1 eq., 1.0 mmol, 227.01 g mol^-1) DDQ was added. After removing the cooling bath, the reaction mixture was stirred at ambient temperature for 3 h, when TLC showed full conversion (n-hexane:EtOAc = 4:1; R_f (3) = 0.32; R_f (2) = 0.40). To the reaction mixture 2 M NaOH solution (28 mL) was added and the layers were separated. The aqueous phase was extracted with DCM (28 mL) three times. The combined organic solution was washed with first water (28 mL) then with brine (40 mL), dried over Na₂SO₄ and evaporated in vacuo. The yellow crude product was purified by recrystallization from ethanol to obtain 0.23 g (69%) 2 as a white solid.

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1H NMR (799.7 MHz, DMSO-d₆, 30 °C) 1.44 (s, 9H, 3×

CH₃-14); 3.02 (br s, 2H, CH₂-1); 3.55 (br s, 2H, CH₂-2);

3.62 (br s, 2H, CH₂-4); 4.30 (br s, 2H, CH₂-5); 6.27 (s, 1H, H-11); 7.18 (dd, J = 8.7; J = 2.0; 1H, CH-8); 7.42 (d, J = 8.7; 1H, CH-7); 7.62 (d, J = 2.0; 1H, CH-10) ppm.

Due to the hindered rotation at the carbamoyl moiety, most signals in the ¹³C spectrum are duplicated, which is indicated by slash mark (/) in the peak list.

13C NMR (201.1 MHz, DMSO-d6, 30 °C) δ 28.0 (3× CH3-14); 29.1/29.5 (CH2-1); 45.4/46.2 (CH2-2); 45.7/45.8 (CH2-5); 46.7/47.5 (CH2-4); 79.2 (C-13); 99.8 (CH-11); 111.26 (CH-7);

111.33 (C-9); 121.5 (CH-10); 122.7 (CH-8); 128.9 (C-10a); 135.7 (C-7a); 142.6 (C-11a);

154.0 (br, C-12) ppm. HRMS: calcd for C17H22O2N2Br [M+H]⁺: 365.08592; found:

365.08563; delta = -0.79 ppm. Mp.: 142-144 ºC (Lit.: N.A.).

4.2.1.7.2. Preparation of 2 from compound 4 using telescoped synthesis

To a solution of 0.67 g (1 eq., 2.2 mmol, 288.385 g mol^-1) 4 in acetonitrile (12 mL), which was cooled to 0 °C under argon atmosphere, solution of 393 mg (1.0 eq., 2.2 mmol, 177.98 g mol^-1) NBS in acetonitrile (6 mL) was added. The reaction mixture was analysed immediately by TLC, which showed full conversion (n-hexane:EtOAc = 4:1; R_f (4) = 0.53; R_f (3) = 0.43). To the reaction mixture, a solution of 0.67 g (1.1 eq., 2.4 mmol, 227.01 g mol^-1) DDQ was added in acetonitrile (9 mL). After removing the cooling bath, the reaction mixture was stirred at ambient temperature for 15 min, when TLC showed full conversion (n- hexane:EtOAc = 4:1; Rf (3) = 0.32; Rf (2) = 0.40). The reaction mixture was evaporated in vacuo and suspended in 2 M NaOH solution (30 mL) and filtered. The residue was washed with 2 M NaOH solution and water. The crude product was purified by recrystallization from ethanol (ca. 3.5 mL) to obtain 0.42 g (52%) 2 as a grey solid. Mp.: 139-140 °C.

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In document Flow Chemistry Techniques in the Development of the Synthesis of Active Pharmaceutical Ingredients and Their (Pldal 81-91)