The Synthesis of 3,3-Dimethyl Aza- and Diazaindolines Using a Palladium-Catalysed Intramolecular Reductive Cyclisation

Abstract

A range of azaindolines was prepared in three steps from heterocyclic amines using halogenation, alkylation with 3-bromo-2-methylpropene, and a palladium-catalysed reductive cyclisation. The chemistry proved applicable to a multigram-scale operation.

Key words

heterocycles - cyclisation - palladium - ring closure - catalysis

• References and Notes

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• 18 Pd(OAc)₂ (0.005 mmol, 2 mol%), Et₃N (0.625 mmol), substrate (0.25 mmol), sodium formate (0.06 M), n-Bu₄NCl (0.25 mmol), and DMF (0.06 M) at 80 °C.
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• 20 General Iodination Procedure NIS (24.75 g, 110.0 mmol) was added to a solution of 2-chloropyridin-4-ylamine (12.85 g, 100.0 mmol) in MeCN (400 mL), and the mixture was stirred and held at reflux overnight. Upon cooling to r.t. the solvent was removed in vacuo and the residue partitioned between EtOAc (250 mL), sat. Na₂S₂O₃ (100 mL), and H₂O (250 mL). The organic layer was separated, washed with H₂O (2 × 250 mL), separated, and the solvent removed in vacuo to afford an orange oil that was subjected to column chromatography on silica gel. Elution with 30–50% EtOAc in PE afforded a pale orange solid that was rinsed with 25% EtOAc in PE (80 mL). The solids were collected by filtration and sucked dry to afford 2-chloro-5-iodopyridin-4-ylamine (7.32 g) as an off-white solid. The mother liquors were concentrated to dryness in vacuo and the residues subjected to column chromatography on silica. Elution with 30–50% EtOAc in PE afforded further pure material (1.90 g). Combined yield 9.22 g, 36%. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.20 (s, 1 H), 6.64 (s, 1 H), 6.50 (br s, 2 H). MS: m/z = 255, 257 [M + H]⁺.
• 21 General Alkylation Procedure KOt-Bu (4.56 g, 40.73 mmol) was added to a stirred solution of 2-chloro-5-iodopyridin-4-ylamine (8.62 g, 33.94 mmol) in anhydrous THF (140 mL), and the mixture was stirred at r.t. for 15 min. 3-Bromo-2-methylpropene (5.51 g, 40.73 mmol) was added, and the mixture was stirred at r.t. overnight. The solvent was removed in vacuo and the residues partitioned between CH₂Cl₂ (100 mL) and H₂O (100 mL). The organic layer was separated, the solvent removed in vacuo, and the residues subjected to column chromatography on silica. Elution with 5–20% EtOAc in PE afforded (2-chloro-5-iodopyridin-4-yl)-(2-methylallyl)amine (7.93 g, 76%) as a pale yellow oil. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.23 (s, 1 H), 6.49 (t, J = 6.4 Hz, 1 H), 6.39 (s, 1 H), 4.84 (s, 1 H), 4.73 (s, 1 H), 3.82 (d, J = 5.7 Hz, 2 H), 1.69 (s, 3 H). MS: m/z = 309, 311 [M + H]⁺.
• 22 General Palladium-Catalysed Cyclisation Pd(OAc)₂ (300 mg, 1.34 mmol), sodium formate (2.40 g, 30.53 mmol), n-Bu₄NCl (8.48 g, 30.53 mmol), and Et₃N (10.6 mL, 76.32 mmol) were added to a solution of (2-chloro-5-iodopyridin-4-yl)-(2-methylallyl)amine (7.85 g, 25.44 mmol) in toluene (200 mL) and H₂O (10 mL), and the mixture was stirred and held at 100 °C under a nitrogen atmosphere overnight. The mixture was filtered whilst still hot and the solids rinsed with toluene (50 mL), H₂O (50 mL), and EtOAc (50 mL). The organic solvent was removed in vacuo, the aqueous residues were diluted with H₂O (100 mL), and extracted with EtOAc (2 × 200 mL). The organic layer was separated, the solvent was removed in vacuo, and the residues subjected to column chromatography on silica. Elution with 30–100% EtOAc in PE afforded 6-chloro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine (4.12 g, 89%) as a colourless solid. ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.72 (s, 1 H), 6.75 (br s, 1 H), 6.33 (s, 1 H), 3.32 (s, 2 H,), 1.25 (s, 6 H). MS: m/z = 183, 185 [M + H]⁺.
• 23 Cyclisation Product (Table 1, Entry 1) ¹H NMR (400 MHz, DMSO-d ₆): δ = 6.94 (d, J = 7.8 Hz, 1 H), 6.57–6.47 (m, 1 H), 6.44 (d, J = 2.0 Hz, 1 H), 5.74 (s, 1 H), 3.21 (d, J = 1.8 Hz, 1 H), 1.20 (s, 6 H). MS: m/z = 182 [M + H]⁺.
• 24 Cyclisation Product (Table 1, Entry 2) ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.72 (s, 1 H), 6.75 (br s, 1 H), 6.33 (s, 1 H), 3.32 (s, 2 H), 1.25 (s, 6 H). MS: m/z = 183 [M + H]⁺.
• 25 Cyclisation Product (Table 1, Entry 3) ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.71 (s, 1 H), 6.74 (s, 1 H), 6.48 (s, 1 H), 3.31 (s, 1 H), 1.25 (s, 6 H). MS: m/z = 228 [M + H]⁺.
• 26 Cyclisation Product (Table 1, Entry 4) ¹H NMR (270 MHz, CDCl₃): δ = 7.09–7.06 (d, J = 8.0 Hz, 1 H), 6.51–6.48 (d, J = 8.0 Hz, 1 H), 5.05 (br s, 1 H), 3.37 (s, 2 H), 1.28 (s, 6 H). MS: m/z = 183 [M + H]⁺.
• 27 Cyclisation Product (Table 1, Entry 5) ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.72–7.64 (m, 1 H), 6.87 (t, J = 2.2 Hz, 1 H), 6.05 (s, 1 H), 3.30 (m, 2 H), 1.20 (s, 6 H). MS: m/z = 228 [M + H]⁺.
• 28 Cyclisation Product (Table 1, Entry 6) ¹H NMR (270 MHz, CDCl₃): δ = 7.74 (s, 1 H), 5.79 (br s, 1 H), 3.46 (s, 2 H), 1.35 (s, 6 H). MS: m/z = 184 [M + H]⁺.
• 29 Cyclisation Product from HCl Deprotection (Table 1, Entry 7) ¹H NMR (270 MHz, CD₃OD): δ = 6.92 (s, 1 H), 3.79 (s, 2 H), 1.44 (s, 6 H). MS: m/z = 184 [M + H]⁺.
• 30 Negishi E.-I. Handbook of Organopalladium Chemistry for Organic Synthesis. Wiley-Interscience; New York: 2002
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• 32 2-Chloro-3-iodopyridin-4-ylamine isolated in 33% yield. ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.75 (d, J = 5.5 Hz, 1 H), 6.53 (m, 3 H), MS: m/z = 255 [M + H]⁺.
• 33 Larger-Scale Palladium Cyclisation To a 10 L flange flask fitted with stirrer bar and nitrogen inlet/outlet was added (2-chloro-5-iodopyridin-4-yl)-(2-methylallyl)amine hydrochloride (217 g, 0.629 mol), Pd(OAc)₂ (7 g, 0.031 mol), sodium formate (51.3 g, 0.755 moles), TBACl (210 g, 0.755 mol), Et₃N (350 mL, 2.52 mol), toluene (4.9 L), and H₂O (242 mL). The reaction mixture was heated at 100 °C (oil bath) overnight after which time NMR confirmed no starting material remaining, bulk material worked up. The reaction mixture was cooled to r.t. and stood overnight. To the cooled reaction mixture was added H₂O (500 mL) and Et₂O (2.5 L), organic layer removed and aqueous re-extracted with Et₂O (1.5 L). Organic extracts combined, washed with sat. brine solution (1.5 L), removed, dried over MgSO₄, filtered, and evaporated to dryness at 40 °C to give 6-chloro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine (76.2 g, 66%) as a yellow solid, the analytical data matched those from the smaller scale.