Studies on Fluorinated Annulated Nicotines: Concise Synthesis of cis-4,4-Difluoro-2,3,3a,4,5,9b-hexahydro-1-methyl-1H-pyrrolo[2,3-f]quinoline

Abstract

A fused 6,6,5-tricyclic difluorinated nicotine analogue was efficiently assembled in five steps in 36% overall yield. The conformation-restricting unit is a six-membered fluorinated carbocycle. The gem-difluoromethylene group was introduced through an indium-promoted Barbier allylation of 3-bromo-3,3-difluoropropene. The construction of the tricyclic skeleton was achieved using an intramolecular azomethine ylide-alkene [3+2] cycloaddition.

Key words

fluorinated - intramolecular azomethine ylide-alkene-[3+2] cycloaddition - nicotine analogue - rigid conformation

References and Notes

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7

The reagent, 3-bromo-3,3-difluoropropene, is available from the TCI Company, although we obtained it as a gift from Professors G. Zhao and F.-L. Qing of the Shanghai Institute of Organic Chemistry (see also Acknowledgment).

12

The acetal deprotection proceeded much faster when the acid used was switched from oxalic acid to TsOH×H₂O.

15

Preparation of New Compounds
Compound 5 Indium powder (67 mg, 0.58 mmol) and 3-bromo-3,3-difluoropropene (70 µL, 0.72 mmol) were added sequen-tially to a solution of 4 (94 mg, 0.45 mmol) in DMF (3 mL). The mixture was then sonicated for 3 h. After evaporation of DMF under reduced pressure, sat. aq NaHCO₃ soln and EtOAc were added. The two layers were separated, and
the aqueous layer was further extracted with EtOAc. The combined organic layers were dried (Na₂SO₄), filtered, and concentrated to give a residue, which was chromatographed (EtOAc-PE, 1:5) to afford 5 (100 mg, 78%) as a colorless oil: ^¹H NMR (300 MHz, CDCl₃): δ = 1.16 (t, J = 9.2 Hz, 3 H), 1.27 (t, J = 9.9 Hz, 3 H), 3.36-3.50 (m, 2 H), 3.54-3.65 (m, 1 H), 3.74-3.82 (m, 1 H), 4.99 (d, J = 9.6 Hz, 1 H), 5.36-5.45 (m, 1 H), 5.49 (d, J = 11.1 Hz, 1 H), 5.61-5.69 (m, 1 H), 5.88 (s, 1 H), 5.92-6.02 (m, 1 H), 7.31 (dd, J = 7.8, 4.5 Hz, 1 H), 8.04 (dd, J = 7.8, 1.5 Hz, 1 H), 8.53 (dd, J = 4.7, 1.7 Hz, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 15.0, 15.0, 60.2, 63.2, 70.4 (t, J = 31.1 Hz), 97.7 (t, J = 4.6 Hz), 120.1 (t, J = 244.8 Hz), 121.1 (t, J = 9.6 Hz), 123.4, 129.8 (t, J = 25.4 Hz), 133.7, 135.6, 147.7, 152.3 (d, J = 5.4 Hz). ^¹9F NMR (282 MHz, CDCl₃): δ = -109.59 (dm, J = 249.2 Hz, 1 F), -104.12 (dm, J = 248.7 Hz, 1 F). MS (MALDI): m/z = 310.1 [M + Na], 289.1 [M + 2H], 288.1
[M + H]. HRMS (MALDI): m/z calcd for C₁₄H₁₉NO₃F₂ + H: 288.1411; found: 288.1414.
Compounds 6a,b To a soln of 5 (108 mg, 0.38 mmol) in acetone and H₂O (1:1, 8 mL) was added PTSA˙H₂O (143 mg, 0.75 mmol). The mixture was heated at reflux for 2 h, cooled to r.t., neutralized with sat. aq NaHCO₃ soln, and extracted with EtOAc. The combined organic layers were dried (MgSO₄), filtered, and concentrated. The residue was chromatog-raphed (EtOAc-PE, 1:1) to give a mixture of 6a and 6b (9:1, 71 mg, 89%) as a colorless oil. ^¹H NMR [300 MHz, CDCl₃, three compounds (two hemiacetals and one aldehyde), 0.49:0.42:0.09]: δ = 3.68 (d, J = 9.6 Hz, 0.42 H, 0.42 OH), 4.46 (d, J = 7.2 Hz, 0.49 H, 0.49 OH), 5.18-5.26 (m, 0.42 H), 5.26-5.29 (m, 0.09 H), 5.38-5.44 (m, 0.49 H), 5.48-2.62 (m, 1 H), 5.82-5.70 (m, 1 H), 5.93-6.07 (m, 0.49 H), 6.12-6.25 (m, 0.42 H), 6.49 (d, J = 9.9 Hz, 0.42 H), 6.65 (d, J = 5.7 Hz, 0.49 H), 7.35-7.39 (m, 0.91 H), 7.56 (dd, J = 7.7, 5.0 Hz, 0.09 H), 7.80-7.84 (m, 0.91 H), 8.28 (d, J = 8.1 Hz, 0.09 H), 8.66-8.69 (m, 0.91 H), 8.80 (d, J = 4.2 Hz, 0.09 H), 10.30 (s, 0.1 H) [0.1 H missing (0.1 OH)]. ^¹9F NMR (282 MHz, CDCl₃): δ = -111.29 (dt, J = 251.4, 11.8 Hz, 0.09 F), -110.33 (dt, J = 251.5, 10.9 Hz, 0.49 F),
-110.13 (dt, J = 251.3, 11.8 Hz, 0.42 F), -108.22 (dt, J = 251.5, 12.4 Hz, 0.42 F), -107.89 (dt, J = 251.3, 9.6 Hz, 0.49 F), -105.58 (dm, J = 251.4 Hz, 0.09 F). MS (EI): m/z (%) = 213 [M⁺], 136 (100). Anal. Calcd for C₁₀H₉F₂NO₂: C, 56.34; H, 4.26; N, 6.57. Found: C, 56.44; H, 4.48; N, 6.70. Compounds 7 A soln of 6 (222 mg, 1.04 mmol) and sarcosine (98%, 139 mg, 1.56 mmol) in toluene (18 mL) was heated at reflux under N₂ overnight, cooled to r.t., and concentrated. The residue was diluted with brine and extracted with EtOAc. The combined organic layers were dried (MgSO₄), filtered, and concentrated. The residue was chromatographed (EtOAc-PE, 1:1) to give a pair of diastereomers of 7 (dr = 9:1, 171 mg, 68%) as a white solid: mp 82-83 ˚C (dec.). ^¹H NMR (300 MHz, CDCl₃): δ = 2.18 (s, 3 H), 2.11-2.30 (m, 1 H), 2.33-2.42 (m, 1 H), 2.45-2.53 (m, 1 H), 2.93-3.07 (m, 1 H), 3.23-3.29 (m, 2 H), 4.75 (d, J = 7.8 Hz, 0.9 H), 5.17 (d, J = 23.4 Hz, 0.1 H), 6.30 (s, 1 H), 7.30-7.34 (dd, J = 7.8, 5.1 Hz, 1 H), 7.54 (d, J = 8.1 Hz, 0.1 H), 7.60 (d, J = 7.5, 1.2 Hz, 0.9 H), 8.56 (d, J = 4.8 Hz, 0.1 H), 8.61 (dd, J = 5.1, 1.2 Hz, 0.9 H). ^¹9F NMR (282 MHz, CDCl₃): δ =
-115.82 (d, J = 238.8 Hz, 0.1 F), -111.39 (dm, J = 249.7 Hz, 0.9 F), -109.14 (dm, J = 238.8 Hz, 0.1 F), -88.52 (dm, J = 249.7 Hz, 0.9 F). ESI-MS: m/z = 483.0 [2M + H], 263.0 [M + Na], 240.9 [M + H]. Anal. Calcd for C₁₂H₁₄F₂N₂O: C, 59.99; H, 5.87; N, 11.66. Found: C, 59.84.; H, 6.06; N, 11.25. Compound 2b To a suspension of NaH (60% in mineral oil, 34 mg, 0.86 mmol) in dry THF (10 mL) under N₂ was added a soln of 7 (103 mg, 0.43 mmol) in dry THF (2 mL). After the mixture was stirred at r.t. for 30 min, CS₂ (80 µL, 1.29 mmol) was added and stirring continued for 1 h. Iodomethane (30 µL, 0.47 mmol) was then added. After stirring for another 0.5 h, the reaction was quenched with sat. aq NaHCO₃ soln and the mixture was extracted with EtOAc. The combined organic layers were dried (Na₂SO₄), filtered, and concentrated. The residue was chromatographed (EtOAc-PE, 1:10) to afford the xanthates (138 mg, 97%) as a colorless oil. To a solution of above-mentioned xanthates (138 mg, 0.42 mmol) in anhyd toluene (36 mL) were added n-Bu₃SnH (97%, 0.14 mL, 0.50 mmol) and AIBN (14 mg, 0.08 mmol). The mixture was stirred at reflux overnight, cooled to r.t., concentrated, diluted with sat. aq NaHCO₃ soln, and extracted with EtOAc. The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated. The residue was chromatographed (EtOAc-PE, 1:1) to afford 2b (74 mg, 79%) as a colorless oil. ^¹H NMR (300 MHz, CDCl₃): δ = 1.79-2.23 (m, 2 H), 2.29-2.41 (m, 1 H), 2.32 (s, 3 H), 2.96-3.13 (m, 2 H), 3.23-3.34 (m, 2 H), 3.60 (dd, J = 33.9, 15.0 Hz, 1 H), 7.21 (dd, J = 7.2, 4.8 Hz, 1 H), 7.49 (d, J = 7.2 Hz, 1 H), 8.49 (d, J = 4.8 Hz, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 25.3 (t, J = 6.0 Hz), 38.4 (t, J = 26.4 Hz), 40.0, 45.0 (dd, J = 26.1, 26.1 Hz), 56.0, 67.3 (d, J = 7.4 Hz), 121.8, 125.9 (dd, J = 244.9, 205.7 Hz), 130.2, 136.4, 148.6, 153.7 (d, J = 11.2 Hz). ^¹9F NMR (282 MHz, CDCl₃): δ = -101.41 (d, J = 242.4 Hz, 1 F), -90.0 (dm, J = 242.4 Hz, 1 F). ESI-MS: 225.2 [M + H]. HRMS (EI): m/z calcd for C₁₂H₁₄N₂F₂: 224.1125; found: 224.1118.