Organic Process Research & Development
Article
hexahydro-1H-benzo[e]indole (24). In a 1000 mL sealed
tube, (3aR,9bR)-3-((S)-tert-butylsulfinyl)-8-fluoro-7-iodo-9b-
(phenylsulfonyl)-2,3,3a,4,5,9b-hexa hydro-1H-benzo[e]indole
36 (11 g, 19 mmol) was taken in DMF (250 mL) and degassed
with argon gas for 10 min. To that were added freshly prepared
copper powder (18.1 g, 285 mmol) and 1,1,1,2,3,3,3-
heptafluoro-2-iodopropane (12.2 mL, 85.3 mmol). The reaction
mixture was then heated at 120 °C for 6 h. On completion, the
reaction mixture was filtered through Celite and the filtrate was
concentrated under reduced pressure to generate a gummy
liquid of the crude product. The crude was taken in ethyl acetate
(100 mL) and washed with 100 mL of water, followed by 75 mL
brine. The combined organic layer was dried over sodium sulfate
and concentrated under vacuum. It was purified by column
chromatography using a 240 g silica column, eluted with 25%
ethyl acetate in hexanes to produce light yellow solids of
(3aR,9bR)-3-((S)-tert-butylsulfinyl)-8-fluoro-7-(perfluoropro-
pan-2-yl)-9b-(phenylsulfonyl)-2,3, 3a,4,5,9b-hexahydro-1H-
benzo[e]-indole 24 (9.6 g, 15.92 mmol, 81% yield). (a)
Analytical data of compound 24 were captured previously. (b)
Analytical data of (3aR, 3′aR, 9bR, 9′bR)-3-((R)-tert-butylsul-
finyl)-3′-(tert-butylsulfinyl)-8,8′-difluoro-9b,9′b-bis-
(phenylsulfonyl)-2,2′,3,3a,3′,3′a,4,4′,5,5′,9b,9′b-dodecahydro-
Nitration of 2,2,2-Trifluoro-1-((3aR,9bR)-7-(perfluoro-
propan-2-yl)-9b-(phenyl sulfonyl)-1,2,3a,4,5,9b-hexahy-
dro-3H-benzo[e]indol-3-yl)ethan-1-one (6). To a pre-
cooled mixture (0 °C) of 2,2,2-trifluoro-1-((3aR,9bR)-7-
(perfluoropropan-2-yl)-9b-(phenylsulfonyl)-1,2,3a,4,5,9b-hexa-
hydro-3H-benzo[e]indol-3-yl)ethan-1-one 6 (500 mg, 0.86
mmol) in conc. sulfuric acid (0.08 ml, 1.47 mmol) was added
potassium nitrate (0.79 mg, 0.079 mmol). The reaction mixture
was then stirred for 16 h at room temperature. After completion,
the reaction was quenched by the slow addition of cold water
(20 mL) and extracted with ethyl acetate (3 × 20 mL). The
combined organic layer was dried over sodium sulfate and
concentrated under reduced pressure to achieve a crude
regioisomeric mixture of nitro compounds (720 mg; 7, 7a,
and 7b). All compounds were purified by preparative HPLC to
achieve light yellow solids of desired 2,2,2-trifluoro-1-
((3aR,9bR)-8-nitro-7-(perfluoropropan-2-yl)-9b-(phenylsul-
fonyl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl) ethan-
1-one 7 (295 mg, 0.47 mmol, 55% yield); 2,2,2-trifluoro-1-
((3aR,9bR)-6-nitro-7-(perfluoropropan-2-yl)-9b-(phenylsul-
fonyl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e] indol-3-yl)ethan-
1-one 7a (107 mg, 0.17 mmol, 20% yield); and 1-((3aR,9bR)-
6,8-dinitro-7-(perfluoropropan-2-yl)-9b-(phenylsulfonyl)-
1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)-2,2,2-trifluor-
oethan-1-one 7b (34 mg, 0.052 mmol, 6% yield). (a) Analytical
data of 2,2,2-trifluoro-1-((3aR,9bR)-8-nitro-7-(perfluoropro-
pan-2-yl)-9b-(phenylsulfonyl)-1,2,3a,4,5,9b-hexahydro-3H-
1
1H,1′H-7,7′-bibenzo[e]indole 37: mp 185.3−185.9 °C; H
NMR (400 MHz, CDCl3): δ 7.65 (t, J = 7.5 Hz, 2H), 7.58 (d, J =
7.5 Hz, 4H), 7.51−7.42 (m, 4H), 7.39−7.31 (m, 2H), 7.07 (t, J
= 5.0 Hz, 2H), 4.47 (dd, J = 4.3, 6.8 Hz, 2H), 3.97−3.83 (m,
2H), 2.99 (td, J = 12.9, 8.6 Hz, 2H), 2.78−2.59 (m, 4H), 2.43
(td, J = 12.5, 4.5 Hz, 2H), 2.31−2.21 (m, 2H), 2.03 (ddd, J =
13.3, 8.8, 4.0 Hz, 2H), 1.73−1.64 (m, 2H), 1.18 (s, 18H). 19F
NMR (376 MHz, CDCl3): δ −116.83. 13C NMR (125 MHz,
CDCl3): δ 157.88 (d, J = 248.0 Hz, 2C), 135.82 (2C), 135.61
(2C), 134.29 (2C), 132.32 (t, J = 3.6 Hz, 2C), 130.86 (2C),
130.35 (4C), 128.80 (4C), 123.31−123.03 (m, 2C), 117.57−
117.26 (m, 2C), 73.46 (2C), 63.73 (2C), 57.49 (2C), 40.13
(2C), 36.87 (2C), 26.89 (2C), 24.47 (2C), 23.42 (6C). HRMS
(ESI) m/z: [M + H]+ calcd for C44H50F2N2O6S4, 869.2598;
found, 869.2602. SOR [α]2D5 (c 0.1, MeOH): +45.60. (c)
Analytical data of (3aR,9bR)-3-((S)-tert-Butylsulfinyl)-8-fluoro-
9b-(phenylsulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]-
indole 38: mp 185.3−185.9 °C; 1H NMR (400 MHz, CDCl3): δ
7.66−7.58 (m, 1H), 7.53−7.47 (m, 2H), 7.46−7.39 (m, 2H),
7.25 (d, J = 10.0 Hz, 1H), 7.05−6.93 (m, 2H), 4.47 (dd, J = 7.5,
4.5 Hz, 1H), 3.90 (ddd, J = 10.4, 8.2, 4.0 Hz, 1H), 3.00 (td, J =
12.8, 8.4 Hz, 1H), 2.72−2.55 (m, 2H), 2.45−2.35 (m, 1H),
2.22−2.08 (m, 1H), 1.94 (td, J = 9.0, 4.5 Hz, 1H), 1.68−1.59
(m, 1H), 1.17 (s, 9H). 19F NMR (376 MHz, CDCl3): δ −115.15
(s, 1F). 13C NMR (125 MHz, CDCl3): δ 161.07 (d, J = 244.3
Hz, 1C), 135.89, 135.73 (d, J = 3.6 Hz, 1C), 134.23, 132.30 (d, J
= 7.3 Hz, 1C), 130.40 (2C), 129.72 (d, J = 7.3 Hz, 1C), 128.79
(2C), 117.00 (d, J = 22.7 Hz, 1C), 115.96 (d, J = 20.9 Hz, 1C),
73.63, 63.87, 57.57, 40.23, 36.86, 27.06, 24.58, 23.54 (3C).
HRMS (ESI) m/z: [M + H]+ calcd for C22H26FNO3S2,
436.1416; found, 436.1419. SOR [α]2D5 (c 0.1, MeOH): −52.40.
(3aR,9bR)-8-Fluoro-7-(perfluoropropan-2-yl)-9b-
(phenylsulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]-
indole (10). It was synthesized following the same protocol as
explained previously. (3aR,9bR)-3-((S)-tert-Butylsulfinyl)-8-
fluoro-7-(perfluoropropan-2-yl)-9b-(phenylsulfonyl)-
2,3,3a,4,5,9b-hexahydro-1H-benzo[e] indole 24 (75 g, 124.4
mmol) resulted in (3aR,9bR)-8-fluoro-7-(per fluoropropan-2-
yl)-9b-(phenylsulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]-
indole 10 (59 g, 118.3 mmol, 95% yield) as white solids.
1
benzo[e]indol-3-yl)ethan-1-one 7: mp 163.3−163.8 °C; H
NMR (400 MHz, DMSO-d6): δ 8.26 (s, 1H), 7.75 (t, J = 7.6 Hz,
1H), 7.53−7.48 (m, 3H), 7.37 (d, J = 7.6 Hz, 2H), 4.86−4.81
(m, 1H), 3.97−3.82 (m, 2H), 3.51−3.40 (m, 1H), 2.92−2.82
(m, 2H), 2.37−2.33 (m, 1H), 1.97−1.89 (m, 1H), 1.54−1.50
(m, 1H). 13C NMR (125 MHz, DMSO-d6): δ 154.31 (q, J = 38.2
Hz, 1C), 147.38, 143.53, 137.50, 135.16, 134.01, 129.46 (3C),
129.38 (2C), 126.50, 119.67 (br q, J = 286.1 Hz, 1C), 119.45 (br
q, J = 287.9 Hz, 1C), 115.77 (q, J = 287.9 Hz, 1C), 115.17,
115.01, 73.33, 60.56, 44.80, 32.74, 26.55, 24.01. 19F NMR (376
MHz, DMSO-d6): δ −71.43 (s, 1F), −74.15, −74.62 (m, 6F),
−183.67 (br s, 1F). LCMS (ESI) m/z: [M + 18]+ calcd for
C23H16F10N2O5S: 640.0; found: 640.0. HRMS (ESI) m/z: [(M
+ H)−(COCF3)•] calcd for C23H16F10N2O5S, 527.0876; found,
527.0884. SOR [α]2D5 (c 0.1, MeOH): −30.40. (b) Analytical
data of 1-((3aR,9bR)-6,8-dinitro-7-(perfluoropropan-2-yl)-9b-
(phenylsulfonyl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e] indol-
1
3-yl)-2,2,2-trifluoroethan-1-one 7b: mp 196.0−196.6 °C; H
NMR (400 MHz, CDCl3): δ 8.60 (d, J = 8.0 Hz, 1H), 8.13 (s,
1H), 8.06−7.94 (m, 2H), 7.88 (t, J = 8.0 Hz, 1H), 7.60 (s, 1H),
4.93 (dd, J = 12.0, 5.2 Hz, 1H), 3.95−3.90 (m, 2H), 3.49−3.41
(m, 1H), 2.95−2.86 (m, 2H), 2.44−2.39 (m, 1H), 2.34−2.25
(m, 1H), 1.58−1.48 (m, 1H). 13C NMR (100 MHz, DMSO-d6):
δ 154.28 (q, J = 36.3 Hz, 1C), 147.76, 147.22 (d, J = 3.6 Hz, 1C),
143.86, 136.81, 135.26 (d, J = 12.4 Hz, 1C), 131.75, 129.58,
126.78, 126.50, 124.35, 119.60 (br q, J = 284.1 Hz, 1C), 119.33
(br q, J = 287.0 Hz, 1C), 115.35 (d, J = 19.6 Hz, 1C), 116.22 (q, J
= 287.7 Hz, 1C), 91.09 (dspt, J = 215.8, 34.9 Hz, 1C), 74.02,
60.22, 44.71 (br q, J = 3.6 Hz, 1C), 33.09, 26.62, 24.12. 19F NMR
(376 MHz, CDCl3): δ −72.44 (s, 1F), −74.52, −74.88 (m, 6F),
−183.28 (br s, 1F). LCMS (ESI) m/z: [M + 18]+ calcd for
C23H15F10N3O7S, 685.0; found, 685.0. HRMS (ESI) m/z: [(M
+ H)-(COCF3)•] calcd for C23H15F10N3O7S, 572.0726; found,
572.0742. SOR [α]2D5 (c 0.1, MeOH): −6.0.
1012
Org. Process Res. Dev. 2021, 25, 1001−1014