Evaluation of Phenyldiazenyl as a Protective/Activating Group in Lithiation–Substitution Reactions of Tetrahydroisoquinolines

Abstract

Phenyldiazenyl moiety has been utilized both as a protective and activating group to synthesize C-1-substituted tetrahydroisoquinolines via lithiation–substitution strategy. This reaction sequence involves generation of α-amino carbanions, derived from N-phenyldiazenyl tetrahydroisoquinolines, followed by coupling with various electrophiles, e.g., aldehyde, ketones, alkyl halide, oxiranes, isocyanates, and with in situ generated arynes. Deprotection of the protecting group was carried out under acidic conditions to afford the desired α-substituted products in moderate to good yields. So, triazene as a protecting/directing group and its compatibility with strong bases provide a good synthetic utility for the synthesis of a variety of α-substituted secondary amines via lithiation substitution reaction.

Key words

phenyldiazene - α-C–H functionalization - C-1-substituted THIQs - α-amino carbanions - electrophiles - nitrogen heterocycles

Publication History

Received: 20 April 2023

Accepted after revision: 07 November 2023

Article published online:
19 December 2023

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• 69 Preparation of 3,4-Dihydro-(1H-isoquinolin-2-yl)-phenyldiazene (3a) The reaction of phenyldiazonium tetrafluoroborate salt (2a, 10 g, 52 mmol) with 1,2,3,4-tetrahydroisoquinoline (1a, 6.9 g, 52 mmol) in pyridine (9.4 mL) according to the general procedure⁵² and subsequent purification gave 3a (7.3 g, 60%) as orange solid; mp 58–60 °C. IR (neat): 3023, 2954, 1667, 1584 (N=N stretching), 1452, 1410, 1297, 1153, 1069, 940, 894, 737, 686 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.51–7.44 (m, 2 H), 7.40–7.31 (m, 2 H), 7.27–7.13 (m, 5 H), 4.95 (s, 2 H), 4.10 (t, J = 6.0 Hz, 2 H), 3.06 (t, J = 6.0 Hz, 2 H). ¹³C NMR (MHz, CDCl₃): δ = 150.88, 134.82, 132.56, 128.80, 128.49,127.21, 126.84, 126.57, 125.79, 120.42, 48.27, 29.59. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₅H₁₅N₃: 238.1338; found: 238.1333.
• 70 Zarei A, Khazdooz L, Aghaei H, Azizi G, Chermahini AN, Hajipour AR. Dyes Pigm. 2014; 101: 295
• 71 Typical Procedure B for α-Lithiation and Substitution of 3 Into a flame-dried two-necked round-bottomed flask, equipped with a magnetic stirrer bar, septum cap, and a bubbler, was taken a solution of (3,4-dihydro-1H-isoquinolin-2-yl)-phenyldiazene (0.5 g) in dry THF (3 mL/mmol) under an inert nitrogen atmosphere. It was cooled to –78 °C and s-BuLi (1.2 equiv) was added dropwise. The deep red color (indicative of benzylic carbanion formation) appeared immediately. The solution was stirred at –78 °C for 30 min, and the electrophile (1.2 equiv) was added slowly at the same temperature. The reaction mixture was allowed to warm gradually up to –40 °C. The reaction was quenched with saturated NH₄Cl solution, and the contents were poured into Et₂O (20 mL). The organic layer was separated, and the aqueous layer was further extracted with Et₂O (2 × 10 mL). The organic layer was washed with brine and dried over anhydrous Na₂SO₄. The solvent was evaporated under reduced pressure to obtain the crude product. Further purification by column chromatography using silica gel over hexane/ethyl acetate (9:1) afforded the desired C-1-substituted product 4.
• 72 Preparation of Diphenyl-(2-phenyldiazenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-methanol (4a)
  Reaction of amine 3a (0.5 g, 2.1 mmol) with benzophenone (0.45 g, 2.5 mmol) according to the general procedure⁷¹ and subsequent purification with flash chromatography using hexane/ethyl acetate (95:5) gave 4a (0.72 g, 82%) as a white solid; mp 140–142 °C. IR (neat): 3394 (O–H stretching), 3054, 3024, 2937, 1595 (N=N stretching), 1485, 1452, 1423, 1351, 1262, 1220, 1187, 1146, 1107, 1055, 1028, 979, 941, 892, 850, 818, 758, 737, 691, 659, 643 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.69–7.65 (m, 2 H), 7.57 (d, J = 7.7 Hz, 2 H), 7.36–7.25 (m, 10 H), 7.19–7.12 (m, 4 H), 6.92–6.85 (m, 1 H), 6.52 (s, 1 H), 4.03 (q, J = 6.6 Hz, 2 H), 2.91 (d, J = 6.7 Hz, 2 H). ¹³C NMR (126 MHz, CDCl₃): δ = 150.50, 143.73, 136.84, 132.27, 128.78, 128.54, 128.20, 127.35, 126.88, 125.81, 120.85, 82.72, 60.46, 27.72. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₅N₃O: 420.2069; found: 420.2071.
• 73 Preparation of 1-Benzoyl-2-phenyldiazenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-phenylmethanone (4g) Reaction of amine 3a (0.5 g, 2.1 mmol) with ethyl benzoate (0.61 mL, 4.2 mmol) according to the general procedure⁷¹ and subsequent purification with flash chromatography using hexane/ethyl acetate (95:5) gave 4g (0.68 g, 72%) as a yellow oil. IR (neat): 3059, 2926, 1715 (C=O stretching), 1668 (C=O stretching), 1596 (N=N), 1494, 1448, 1427, 1372, 1245, 1229, 1157, 1123, 1026, 1000, 922, 828, 744, 718, 692, 636 cm^–1. ¹H NMR (500 MHz, DMSO): δ = 7.74–7.69 (m, 2 H), 7.51–7.49 (m, 3 H), 7.46–7.38 (m, 4 H), 7.38–7.22 (m, 8 H), 7.11–7.06 (m, 2 H), 6.74 (dd, J = 17.5, 11.0 Hz, 1 H), 5.70 (dd, J = 17.5, 1.3 Hz, 1 H), 5.12 (dd, J = 11.0, 1.2 Hz, 1 H), 4.03 (m, J = 7.1 Hz, 1 H). ¹³C NMR (126 MHz, DMSO): δ = 170.16, 143.71, 136.40, 136.11, 135.27, 134.23, 131.66, 130.95, 129.54, 129.27, 128.93, 128.69, 128.29, 127.49, 126.47, 125.43, 125.02, 121.87, 115.23, 113.62, 59.58, 42.42, 27.56.
• 74 General Procedure C for the Deprotection of 4/7 Using Trifluoroacetic Acid (TFA)⁵² Into a 50 mL round-bottom flask equipped with magnetic bar and guard tube was taken a solution of 4/7 (100 mg, 1 equiv) in dry ethanol (2 mL/mmol). The solution was cooled to 0 °C, and trifluoroacetic acid (TFA, 20 equiv) was added slowly to the solution. The reaction mixture was allowed to warm to room temperature and further stirred overnight. Solvent was evaporated under reduced pressure. The residue, so obtained, was basified with 20% potassium hydroxide solution and extracted with chloroform (4 × 10 mL). The organic layer was washed with brine and dried over anhydrous Na₂SO₄. The solvent was evaporated in vacuo to afford the crude deprotected product. Purification by flash chromatography using 230–400 silica gel using chloroform/methanol (9:1) to afford α-substituted product 5 and 8.
• 75 Preparation of Phenyl-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-diazene (7a) Reaction of amine 3a (0.5 g, 2.1 mmol) with chlorobenzene (6a, 0.64 mL, 6.3 mmol) according to the general procedure⁷⁶ and subsequent purification with flash chromatography using hexane/ethyl acetate (95:5) gave 7a as a yellow oil (0.42 g, 65%). IR (neat): 3026, 2874, 1590 (N=N), 1484, 1412, 1350, 1167, 1103, 1069, 1024, 911, 865, 757, 731, 713, 689 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.40 (d, J = 8.0 Hz, 2 H), 7.27 (t, J = 7.7 Hz, 2 H), 7.18 (q, J = 8.9 Hz, 9 H), 7.08 (t, J = 7.3 Hz, 1 H), 6.58 (s, 1 H), 4.13 (dt, J = 13.7, 6.8 Hz, 1 H), 3.93–3.86 (m, 1 H), 2.99 (dt, J = 13.5, 6.2 Hz, 1 H), 2.84 (dt, J = 15.3, 6.3 Hz, 1 H). ¹³C NMR (126 MHz, CDCl₃): δ = 141.57, 135.27, 128.95, 128.85, 128.47, 128.15, 127.79, 127.54, 127.37, 126.57, 125.68, 120.72, 53.43, 43.27, 27.88. HRMS (ESI): m/z [M + H]⁺: C₂₁H₁₉N₃ calcd for 314.1651; found: 314.1653.
• 76 General Procedure for Arylation of 3 Into a flame-dried two-necked round-bottomed flask (50 mL), equipped with a magnetic stirrer bar, septum cap, and a bubbler, was taken a solution of (3,4-dihydro-1H-isoquinolin-2-yl)-phenyldiazene (3, 0.5 g) in dry THF (3 mL/mmol) under an inert nitrogen atmosphere. It was cooled to –78 °C, and s-BuLi (1.2 equiv) was added. A deep red color, which is indicative of benzylic carbanion formation, appeared immediately. The solution was stirred at the same temperature for 30 min. The second installment of s-BuLi (3 equiv) was added, followed by addition of a solution of arylhalide 6 (3 equiv) in THF (1 mL). The reaction mixture was stirred at –78 °C for 30 min and was allowed to warm to 0 °C slowly over a period of 4–5 h. The reaction was quenched with saturated NH₄Cl solution, and the contents were poured into Et₂O (20 mL). The organic layer was separated, and the aqueous layer was further extracted with Et₂O (2 × 10 mL). The organic layer was washed with brine and dried over anhydrous Na₂SO₄. The solvent was evaporated under reduced pressure to afford the crude product which was purified by flash chromatography using 230–400 mesh silica gel. Elution with ethyl acetate/hexane (1:9) afforded the product 7.