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Synlett 2009(12): 1955-1958  
DOI: 10.1055/s-0029-1217519
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Bin Chenga,b, Hongbin Zhai*a,b
a Hefei National Laboratory for Physical Science at Microscale and Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, P. R. of China
b Key Laboratory of Synthetic Chemistry of Natural Substances and State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. of China
e-Mail: +86(21)64166128; e-Mail: zhaih@mail.sioc.ac.cn;
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Publication History

Received 4 March 2009
Publication Date:
25 June 2009 (online)

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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

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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).

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

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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.