The Journal of Organic Chemistry
Article
MHz, DMSO-d6) δ = 21.7, 26.6, 28.2, 44.7, 56.1, 68.2, 80.1, 108.2,
(6R,13S,13aS)-13-[(3-Methylbut-2-en-1-yl)oxy]-1,2,3,6,-
7,12,13,13a-octahydro-5H-6,13-epiminopyrrolo[1′,2′:1,2]azocino-
[4,5-b]indol-5-one (14d). Following general procedure B using 1.5
equiv of prenyl alcohol, 14d was obtained after purification by
reversed-phase chromatography (2 column volumes (CVs) of 9:1
H2O/ACN, over 16 CVs to 6:4 H2O/ACN, then 8 CVs of 6:4 H2O/
ACN) as a yellow powder: yield 33% (58 mg); yellow powder; mp
̃
111.5, 118.1, 118.3, 121.0, 126.1, 133.6, 136.0, 169.9 ppm; IR ν = 3262
(NH), 1593 (CO), 1452; MS (ES) m/z (rel intens, %) = 284 (100)
[M + H]+; HRMS (ESI) calcd for C16H18N3O2+ [M + H]+ 284.1394,
found 284.1401.
Procedure for the Synthesis of (6R,13S,13aS)-13-Methoxy-
1,2,3,6,7,12,13,13a-octahydro-5H-6,13-epiminopyrrolo-
[1′,2′:1,2]azocino[4,5-b]indol-5-one (14b). α-Chloroamine 12d (1
equiv, 1 mmol, 302 mg) was suspended in MeOH (10 mL). A sodium
methoxide solution in MeOH (1 equiv, 1 mmol, 0.25 mL of 4 M
solution) was added, and the mixture was refluxed for 2.5 h. Next, the
mixture was quenched by the addition of water, and the solvent was
concentrated under reduced pressure. The residual white precipitate
was redissolved in chloroform (10 mL) and washed three times with
water. After the organic phase was dried over MgSO4, the solvent was
removed by evaporation to give compound 14b as a white solid
(96%): yield 96% (285 mg); white solid; mp >260 °C; [α]2D0 = −69.8
(c = 0.35 in CHCl3); 1H NMR (400 MHz, CDCl3) δ = 1.55−1.68 (m,
1H), 1.72−1.86 (m, 1H), 1.92−2.04 (m, 2H), 2.23 (s, 1H), 2.93 (ddd,
J = 12.2 Hz, J = 10.1 Hz, J = 4.8 Hz, 1H), 3.02 (dd, J = 15.9 Hz, J = 1.3
Hz, 1H), 3.20 (dd, J = 15.9 Hz, J = 6.5 Hz, 1H), 3.35 (s, 3H), 3.58 (dd,
J = 11.8 Hz, J = 4.9 Hz, 1H), 3.94−4.03 (m, 1H); 4.17 (dd, J = 6.5 Hz,
J = 1.3 Hz, 1H), 7.13 (ddd, J = 7.8 Hz, J = 7.8 Hz, J = 1.0 Hz, 1H),
7.21 (ddd, J = 7.8 Hz, J = 7.8 Hz, J = 1.0 Hz, 1H), 7.36 (d, J = 7.8 Hz,
1H), 7.50 (d, J = 7.8 Hz, 1H), 8.09 (s, 1H) ppm; 13C NMR (100
MHz, CDCl3) δ = 21.5, 24.4, 25.5, 43.5, 51.3, 57.8, 66.6, 83.6, 111.2,
1
116−124 °C; [α]2D0 = −66.5 (c = 0.53 in CHCl3); H NMR (400
MHz, CDCl3) δ = 1.53 (s, 3H), 1.57−1.70 (m, 1H), 1.73 (s, 3H),
1.71−1.84 (m, 1H), 1.93−2.04 (m, 2H), 2.31 (s, 1H), 2.88−2.96 (m,
1H), 3.02 (d, J = 15.9 Hz, 1H), 3.20 (dd, J = 15.9 Hz, J = 6.0 Hz, 1H),
3.58 (dd, J = 11.8 Hz, J = 4.9 Hz, 1H), 3.90−4.02 (m, 2H), 4.17 (d, J =
6.0 Hz, 1H), 4.27 (dd, J = 11.9 Hz, J = 6.5 Hz, 1H), 5.34 (t, J = 6.5 Hz,
1H), 7.12 (dd, J = 7.7 Hz, J = 7.7 Hz, 1H), 7.21 (dd, J = 7.7 Hz, J = 7.7
Hz, 1H), 7.35 (d, J = 7.7 Hz, 1H), 7.35 (d, J = 7.7 Hz, 1H), 8.10 (s,
1H) ppm; 13C NMR (100 MHz, CDCl3) δ = 18.1, 21.5, 24.5, 25.6,
25.8, 43.6, 57.9, 60.7, 66.7, 83.4, 110.9, 111.2, 119.0, 119.9, 121.3,
̃
122.7, 126.9, 133.8, 136.1, 136.5, 171.3 ppm; IR ν = 3252 (NH), 1627
(CO), 1446; MS (ES) m/z (rel intens, %) = 352 (100) [M + H]+,
+
703 (30); HRMS (ESI) calcd for C21H26N3O2 [M + H]+ 352.2020,
found 352.2029.
(6R,13R,13aS)-13-(Allylamino)-1,2,3,6,7,12,13,13a-octahydro-5H-
6,13-epiminopyrrolo[1′,2′:1,2]azocino[4,5-b]indol-5-one (14e).
Using general procedure B using 3 equiv of allylamine, compound
14e was obtained without further purification: yield 77% (124 mg);
yellow powder; mp 206−210 °C; [α]2D0 = −28.3 (c = 0.34 in CHCl3);
1H NMR (400 MHz, CDCl3) δ = 1.50−1.73 (m, 2H), 1.73−1.88 (m,
1H), 1.88−1.97 (m, 1H), 1.97−2.12 (m, 2H), 2.94 (ddd, J = 12.2 Hz, J
= 10.2 Hz, J = 4.6 Hz, 1H), 3.03 (dd, J = 16.1 Hz, J = 1.4 Hz, 1H),
3.02−3.13 (m, 1H), 3.13 (dd, J = 16.1 Hz, J = 6.4 Hz, 1H), 3.39 (ddt, J
= 14.6 Hz, J = 6.4 Hz, J = 1.5 Hz, 1H), 3.50 (dd, J = 11.9 Hz, J = 4.6
Hz, 1H), 4.01 (ddd, J = 12.2 Hz, J = 9.5 Hz, J = 6.2 Hz, 1H), 4.18 (dd,
J = 6.4 Hz, J = 1.4 Hz, 1H), 5.11 (ddt, J = 10.3 Hz, J = 1.5 Hz, J = 1.5
Hz, 1H), 5.23 (ddt, J = 17.1 Hz, J = 1.5 Hz, J = 1.5 Hz, 1H), 5.92
(dddd, J = 17.1 Hz, J = 10.3 Hz, J = 6.4 Hz, J = 4.8 Hz, 1H), 7.11 [ddd,
J = 7.7 Hz, J = 7.7 Hz, J = 1.0 Hz, 1H), 7.19 (ddd, J = 7.7 Hz, J = 7.7
Hz, J = 1.0 Hz, 1H), 7.35 (d, J = 7.7 Hz, 1H), 7.49 (d, J = 7.7 Hz, 1H),
8.20 (s, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ = 21.5, 25.1 (2
carbons), 43.2, 44.7, 57.1, 67.1, 67.8, 110.0, 111.2, 115.6, 118.8, 119.7,
̃
111.3, 119.0, 120.0, 122.8, 126.9, 133.2, 136.1, 171.3 ppm; IR ν = 3150
(NH), 1620 (CO), 1462; MS (ES) m/z (rel intens, %) = 298 (100)
+
[M + H]+, 595 (75); HRMS (ESI) calcd for C17H20N3O2 [M + H]+
298.1550, found 298.1556.
General Procedure B: Synthesis of Derivatives 14c−j. The
nucleophile (3 equiv, 1.5 mmol, or 1.5 equiv, 0.75 mmol) was
dissolved in THF (10 mL) at room temperature. The solution was
cooled to 0 °C, and sodium hydride (3 equiv, 1.5 mmol, 60 mg, or 1.5
equiv, 0.75 mmol, 30 mg, respectively, 60% in mineral oil) was added.
After the resulting mixture was stirred for 15 min at 0 °C, α-
chloroamine 12 (1 equiv, 0.5 mmol, 151 mg) was added to it. The
mixture was allowed to warm to room temperature and was kept
stirring until the conversion was complete. An ammonia chloride
solution (10 mL) and ethyl acetate (15 mL) were added subsequently.
The layers were separated, and the aqueous phase was extracted with
10 mL of ethyl acetate. The combined organic phases were washed
three times with water (10 mL). The organic phase was dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure to remove the solvent. When necessary, further purification
was done by chromatography using (a mixture of) ethyl acetate (and
methanol) as the eluent to provide the desired compound.
(6R,13S,13aS)-13-(Allyloxy)-1,2,3,6,7,12,13,13a-octahydro-5H-
6,13-epiminopyrrolo[1′,2′:1,2]azocino[4,5-b]indol-5-one (14c).
Using general procedure B with 3 equiv of allyl alcohol, compound
14c was obtained without further purification: yield 86% (140 mg);
yellow powder; mp 258−260 °C; [α]2D0 = −28.4 (c = 0.32 in CHCl3);
1H NMR (400 MHz, CDCl3) δ = 1.58−1.71 (m, 1H), 1.71−1.83 (m,
1H), 1.91−2.05 (m, 2H), 2.60 (s, 1H), 2.90 (ddd, J = 12.1 Hz, J = 10.3
Hz, J = 4.6 Hz, 1H), 3.01 (dd, J = 15.9 Hz, J = 1.0 Hz, 1H), 3.18 (dd, J
= 15.9 Hz, J = 6.4 Hz, 1H), 3.61 (dd, J = 11.7 Hz, J = 4.9 Hz, 1H), 3.92
(ddt, J = 13.7 Hz, J = 5.1 Hz, J = 1.7 Hz, 1H), 3.96 (ddd, J = 12.1 Hz, J
= 9.4 Hz, J = 6.1 Hz, 1H), 4.15 (dd, J = 5.1 Hz, J = 1.0 Hz, 1H), 4.31
(ddt, J = 13.7 Hz, J = 4.9 Hz, J = 1.7 Hz, 1H), 5.14 (ddt, J = 10.5 Hz, J
= 1.7 Hz, J = 1.7 Hz, 1H), 5.28 (ddt, J = 17.1 Hz, J = 1.7 Hz, J = 1.7
Hz, 1H), 5.92 (dddd, J = 17.1 Hz, J = 10.5 Hz, J = 5.1 Hz, J = 4.9 Hz,
1H), 7.10 (ddd, J = 7.7 Hz, J = 7.7 Hz, J = 0.6 Hz, 1H), 7.18 (ddd, J =
7.7 Hz, J = 7.7 Hz, J = 0.6 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.48 (d, J
= 7.7 Hz, 1H), 8.45 (s, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ =
21.5, 24.4, 25.6, 43.6, 57.9, 64.4, 66.7, 83.6, 110.8, 111.4, 115.6, 119.0,
̃
122.5, 127.3, 134.9, 135.6, 136.9, 170.9 ppm; IR ν = 3273 (NH), 1613
(CO), 1455; MS (ES) m/z (rel intens, %) = 323 (100) [M + H]+;
HRMS (ESI) calcd for C19H23N4O+ [M + H]+ 323.1866, found
323.1881.
(6R,13S,13aS)-13-(Allylthio)-1,2,3,6,7,12,13,13a-octahydro-5H-
6,13-epiminopyrrolo[1′,2′:1,2]azocino[4,5-b]indol-5-one (14f).
Using general procedure B using 3 equiv of allyl mercaptan, 14f was
obtained after purification by pTLC as a white powder: yield 32% (55
mg); white powder; Rf = 0.22 (EtOAc); mp 136−140 °C; [α]D20
=
−165.26 (c = in CHCl3); 1H NMR (400 MHz, CDCl3) δ = 1.63−1.76
(m, 1H), 1.76−1.87 (m, 1H), 1.91−1.99 (m, 1H), 1.99−2.07 (m, 1H),
2.45 (s, 1H), 2.95 (ddd, J = 12.2 Hz, J = 10.2 Hz, J = 4.6 Hz, 1H), 3.01
(dd, J = 16.0 Hz, J = 1.3 Hz, 1H), 3.02 (ddt, J = 13.6 Hz, J = 7.4 Hz, J
= 1.2 Hz, 1H), 3.16 (dd, J = 16.0 Hz, J = 6.5 Hz, 1H), 3.29 (ddt, J =
13.3 Hz, J = 7.0 Hz, J = 1.2 Hz, 1H), 3.58 (dd, J = 11.9 Hz, J = 4.7 Hz,
1H), 3.99 (ddd, J = 12.2 Hz, J = 9.5 Hz, J = 6.3 Hz, 1H), 4.06 (dd, J =
6.5 Hz, J = 1.3 Hz, 1H), 5.01 (ddt, J = 9.9 Hz, J = 1.2 Hz, J = 1.2 Hz,
1H), 5.04 (ddt, J = 17.0 Hz, J = 1.2 Hz, J = 1.2 Hz, 1H), 5.79 (dddd, J
= 17.0 Hz, J = 9.9 Hz, J = 7.4 Hz, J = 7.0 Hz, 1H), 7.13 (ddd, J = 7.8
Hz, J = 7.8 Hz, J = 1.1 Hz, 1H), 7.21 (ddd, J = 7.8 Hz, J = 7.8 Hz, J =
1.1 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 8.16 (s,
1H) ppm; 13C NMR (100 MHz, CDCl3) δ = 21.7, 24.8, 26.2, 31.9,
43.1, 55.9, 63.1, 67.0, 110.4, 111.2, 117.9, 118.9, 120.0, 122.7, 127.2,
134.0, 134.3, 135.5, 170.9 ppm; IR ν
̃
= 3262 (NH), 1614 (CO),
1448; MS (ES) m/z (rel intens, %) = 340 (100) [M + H]+, 679 (25);
HRMS (ESI) calcd for C19H22N3OS+ [M + H]+ 340.1478, found
340.1490.
̃
119.9, 122.7, 126.9, 133.6, 135.3, 136.2, 171.4 ppm; IR ν = 3266
(6R,13S,13aS)-13-Phenoxy-1,2,3,6,7,12,13,13a-octahydro-5H-
6,13-epiminopyrrolo[1′,2′:1,2]azocino[4,5-b]indol-5-one (14g). Fol-
lowing general procedure B using 3 equiv of phenol, 14g was obtained
as the insoluble residue from rinsing the crude with acetone and
(NH), 1628 (CO), 1457; MS (ES) m/z (rel intens, %) = 324 (100)
+
[M + H]+, 647 (65); HRMS (ESI) calcd for C19H22N3O2 [M + H]+
324.1707, found 324.1700.
G
J. Org. Chem. XXXX, XXX, XXX−XXX