D
F. V. Rossi et al.
Paper
Synthesis
(1.722 g, 15 mmol). The resulting reaction mixture was stirred at the
same temperature for 30 min. Afterwards, the temperature was left to
reach r.t. and the system was stirred for an additional 3.5 h (moni-
tored by GC). Successively, the solvent was evaporated under vacuum,
the residue was dissolved in EtOAc (50 mL), and treated with sat. aq
NaHCO3 (30 mL). The two layers were separated and the aqueous lay-
er was extracted with EtOAc (2 × 50 mL). The combined organic layers
were dried (Na2SO4), filtered, and the solvent evaporated under re-
duced pressure. The resulting crude product was purified by column
chromatography (EtOAc/MeOH 95:5) to give pure amine 3 in 91%
yield (9.08 mmol, 1.710 g); pale yellow oil.
of Grubbs 1st generation catalyst (0.329 g, 0.4 mmol) was added and
the resulting mixture was stirred at the same temperature for an ad-
ditional 3 h. Successively, the reaction mixture was treated with sat.
aq NaHCO3 (30 mL), the two layers were separated, and the aqueous
layer was extracted with CH2Cl2 (2 × 30 mL). The combined organic
layers were dried (Na2SO4), filtered, and the solvent was evaporated
under reduced pressure. The resulting crude product was purified by
column chromatography (hexane/EtOAc 60:40) to give pure 5 in 85%
yield (6.8 mmol, 1.772 g); yellow oil.
IR (neat): 713, 1107, 1165, 1403, 1688 cm–1
.
1H NMR (400 MHz, DMSO-d6, 60 °C): δ = 1.43 [s, 9 H, (CH3)3C], 2.56
(dd, J = 17.7, 5.7 Hz, 1 H, H-3b), 2.64 (m, 1 H, H-3a), 3.35 (br d, J = 18.8
Hz, 1 H, H-6b), 4.13 (br d, J = 18.8 Hz, 1 H, H-6a), 5.45 (d, J = 6.1 Hz, 1
H, H-2), 5.71 (m, 1 H, H-5), 5.87 (m, 1 H, H-4), 7.33 (dd, J = 7.9, 4.8 Hz,
1 H, H-5′), 7.61 (br d, J = 7.9 Hz, 1 H, H-4′), 8.45 (dd, J = 4.8, 1.4 Hz, 1 H,
H-6′), 8.46 (d, J = 2.2 Hz, 1 H, H-2′).
13C NMR (100 MHz, DMSO-d6, 60 °C): δ = 27.3 (C-3′), 27.8 [CH3)3C],
40.2 (C-6), 48.5 (C-2), 79.2 [CH3)3C], 122.7 (C-4), 123.0 (C-5′), 124.0
(C-5), 133.7 (C-4′), 136.5 (C-3′), 147.7 (C-2′), 147.8 (C-6′), 154.0 (C=O).
IR (neat): 715, 915, 993, 1424, 1460, 1576, 1641, 3077 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.84 (br s, 1 H), 2.36–2.44 (m, 2 H),
2.99 (ddt, J = 14.1, 6.8, 2.6 Hz, 1 H), 3.08 (ddt, J = 14.1, 5.5, 1.7 Hz, 1 H),
3.73 (t, J = 6.8 Hz, 1 H), 5.02–5.12 (m, 4 H), 5.62–5.73 (m, 1 H), 5.75–
5.86 (m, 1 H), 7.24 (d, J = 7.3, 4.3 Hz, 1 H), 7.66 (dt, J = 7.7, 2.1 Hz, 1 H),
8.47 (dd, J = 4.7, 1.7 Hz, 1 H), 8.50 (d, J = 2.1 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 43.0, 50.2, 59.4, 116.4, 118.6, 123.7,
134.7, 135.0, 136.6, 139.1, 148.9, 149.7.
MS (EI): m/z = 148, 147 (100%), 130, 117, 105, 78, 41.
MS (EI): m/z = 260 (M+), 204 (100%), 159, 144, 106, 79, 57, 41.
Anal. Calcd for C12H16N2 (188.27): C, 76.55; H, 8.57; N, 14.88. Found:
C, 76.59; H, 8.52; N, 14.91.
Anal. Calcd for C15H20N2O2 (260.34): C, 69.20; H, 7.74; N, 10.76.
Found: C, 69.24; H, 7.77; N, 10.73.
Step III: tert-Butyl Allyl[1-(pyridin-3-yl)but-3-en-1-yl]carbamate
Step V: Anatabine (6)
(4)
In a 100 mL round-bottomed flask, TFA (5 mL) was slowly added to a
stirred solution of compound 5 (0.781 g, 3 mmol) in CH2Cl2 (5 mL),
and the resulting mixture was stirred at r.t. for 3 h. Then, the solvent
and TFA were evaporated under vacuum, the residue was dissolved in
THF (5 mL) and treated with aq 5 M solution of NaOH (5 mL). The re-
sulting mixture was stirred at r.t. for 2 h, then the two layers were
separated, and the aqueous layer was extracted with CH2Cl2 (2 × 50
mL). The combined organic layers were dried (Na2SO4), filtered, and
the solvent was evaporated under reduced pressure. The resulting
crude product was purified by column chromatography (CHCl3/MeOH
8:2) to give pure anatabine (6) in 93% yield (2.8 mmol, 0.449 g); pale
yellow oil.
In a 250 mL round-bottomed flask, K2CO3 (2.211 g, 16 mmol) was
added to a stirred solution of amine 3 (1.506 g, 8 mmol) and di-tert-
butyl dicarbonate (3.492 g, 16 mmol) in 2-MeTHF (60 mL). The result-
ing reaction mixture was stirred at 50 °C for 24 h, then it was cooled
to r.t. and treated with H2O (40 mL). The two layers were separated
and the aqueous layer was extracted with EtOAc (2 × 50 mL). The
combined organic layers were dried (Na2SO4), filtered, and the solvent
evaporated under reduced pressure. The resulting crude product was
purified by column chromatography (hexane/EtOAc 60:40) to give the
pure Boc protected amine 4 in 98% yield (7.83 mmol, 2.258 g); clear
oil.
IR (neat): 733, 914, 1145, 1169, 1397, 1684, 3083 cm–1
.
IR (neat): 638, 663, 713, 804, 1424, 1577, 1655, 3029, 3262 cm–1
.
1H NMR (400 MHz, DMSO-d6, 60 °C): δ = 1.39 [s, 9 H, (CH3)3C], 2.78 (br
d, J = 6.8 Hz, 1 H, H-2b), 2.79 (br d, J = 6.8 Hz, 1 H, H-2a), 3.67 (dd, J =
16.0, 6.1 Hz, 1 H, H-1′b), 3.73 (dd, J = 16.0, 6.1 Hz, 1 H, H-1′a), 4.95 (br
d, J = 9.8 Hz, 1 H, H-3′b), 4.98 (br d, J = 16.7 Hz, 1 H, H-3′a), 5.06 (br d,
J = 10.2 Hz, 1 H, H-4b), 5.14 (br d, J = 17.3 Hz, 1 H, H-4a), 5.15 (br s, 1
H, H-1), 5.61 (m, 1 H, H-2′), 5.77 (m, 1 H, H-3), 7.35 (dd, J = 7.9, 4.8 Hz,
1 H, H-5′′), 7.74 (br d, J = 7.9 Hz, 1 H, H-4′′), 8.47 (dd, J = 4.8, 1.5 Hz, 1
H, H-6′′), 8.55 (d, J = 2.4 Hz, 1 H, H-2′′).
13C NMR (100 MHz, DMSO-d6, 60 °C): δ = 27.8 [CH3)3C], 34.5 (C-2),
46.5 (C-1′), 56.3 (C-1), 78.9 [CH3)3C], 115.7 (C-3′), 117.0 (C-4), 122.9
(C-5′′), 134.8 (2 C, C-3 + C-4′′), 135.1 (C-2′), 135.7 (C-3′′), 148.0 (C-6′′),
148.8 (C-2′′), 154.4 (C=O).
1H NMR (400 MHz, CDCl3): δ = 2.21–2.32 (m, 2 H), 2.82 (s, 1 H), 3.44–
3.67 (m, 2 H), 3.90 (dd, J = 8.1, 6.0 Hz, 1 H), 5.75–5.91 (m, 2 H), 7.24–
7.30 (m, 1 H), 7.74 (d, J = 8.1 Hz, 1 H), 8.5 (d, J = 4.3 Hz, 1 H) 8.61 (d, J =
2.1 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 33.9, 46.0, 55.5, 123.8, 125.4, 126.2,
134.5, 139.7, 148.9, 149.1.
MS (EI): m/z = 160 (M+, 100%), 159, 145, 131, 105, 80, 54, 39.
Anal. Calcd for C10H12N2 (160.22): C, 74.97; H, 7.55; N, 17.48. Found:
C, 75.01; H, 7.58; N, 17.45.
Funding Information
MS (EI): m/z = 247, 191, 147 (100%), 57, 41.
Anal. Calcd for C17H24N2O2 (288.39): C, 70.80; H, 8.39; N, 9.71. Found:
C, 70.77; H, 8.42; N, 9.73.
This work was supported by the University of Camerino and Indena
S.p.a.
)(
Step IV: tert-Butyl 3,6-Dihydro-[2,3′-bipyridine]-1(2H)-carboxyl-
ate (5)
Acknowledgment
In a 100 mL round-bottomed flask, compound 4 (2.307 g, 8 mmol)
was dissolved in anhyd CH2Cl2 (40 mL) and treated with p-TsOH·H2O
(1.674 g, 8.8 mmol) and the solution was stirred for 1 h at r.t. Then, 5%
The authors thank Dr. Daniele Ciceri (Indena S.p.A.) for valuable dis-
cussion.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–E