1909
J. Gogoi et al.
Paper
Synthesis
internal standards. Hydrogenation reactions were performed in a Parr
Baldor hydrogenation apparatus. ESI mass spectra (LC) were recorded
on a Bruker Daltonic Data Analysis 2–0 spectrometer. EI (GC) mass
spectra were recorded in a Finnigan Trace DSQ GC/MS instrument
(Thermo Fisher Scientific) using a direct insertion probe. Elemental
analysis was performed by using a PerkinElmer Series II CSNS/O Mod-
el 2400 machine calibrated against acetanilide as a standard. Yields
refer to chromatographically purified compounds unless otherwise
stated.
1H NMR (300 MHz, CDCl3): δ = 7.56 (s, 1 H), 5.71 (br s, 2 H), 5.40 (d,
J = 4.5 Hz, 1 H), 4.53–4.69 (m, 1 H), 2.04 (s, 3 H), 1.50–2.70 (m, 17 H),
1.09 (s, 3 H), 1.01 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 176.8, 170.6, 159.0, 140.1, 137.5, 125.7,
121.8, 117.4, 87.9, 73.8, 55.4, 50.3, 46.2, 38.1, 36.8, 33.8, 32.9, 31.2,
30.6, 29.3, 27.7, 20.4, 19.3, 16.9.
LC/MS (ESI): m/z = 406 [M + 1]+.
Anal. Calcd for C25H31N3O2: C, 74.04; H, 7.70; N, 10.36. Found: C,
74.10; H, 7.65; N, 10.35.
β-Bromo α,β-Unsaturated Aldehydes 1; General Procedure
(6aS,11aS)-8-Amino-9-cyano-6a-methyl-5,6,6a,11,11a,11b,12,13-
octahydro-4bH-naphtho[2′,1′:4,5]indeno[1,2-b]pyridin-2-yl Ace-
tate (3c)
A mixture of DMF (5 mmol) and anhyd CHCl3 was cooled in an ice
bath, and PBr3 (2 mmol) was added dropwise over 10 min. The result-
ing white suspension was warmed to r.t. and stirred for another 30
min. A solution of the appropriate carbonyl compound (1 mmol) in
CHCl3 (7 mL) was added dropwise and the mixture was stirred for 12
h at r.t. The mixture was then poured into ice-water. Solid NaHCO3
was carefully added to neutralize the acids and the mixture was ex-
tracted with CH2Cl2 (3 × 10 mL). The organic phases were combined,
washed with cold H2O (2 × 10 mL), dried (Na2SO4), and concentrated.
The residue was purified by column chromatography [silica gel (60–
120 mesh)]. All the products were characterized; detailed characteri-
zation data are reported in our previous publications.22
White solid; yield: 310 mg (80%); mp 256–258 °C; Rf = 0.5 (20%
EtOAc–hexanes).
IR (CHCl3): 3370, 3218, 2925, 2854, 2215, 1702, 1609, 1425, 1493,
768 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.50 (s, 1 H), 7.15 (d, J = 8.4 Hz, 1 H),
6.65 (dd, J1 = 2.4, J2 = 8.4 Hz, 1 H), 6.59 (d, J = 2.1 Hz, 1 H), 5.57 (s, 2 H),
2.10 (s, 3 H), 1.59–3.00 (m, 13 H), 0.96 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 177.1, 174.9, 159.0, 153.2, 137.6,
136.8, 131.6, 125.8, 125.2, 117.1, 114.9, 112.4, 87.2, 54.2, 46.2, 43.7,
37.0, 32.6, 28.9, 28.6, 28.5, 26.8, 25.7, 16.7.
β-Bromo-α-Formylidenemalononitriles 2; General Procedure
LC/MS (ESI): m/z = 387 [M+].
A mixture of the appropriate β-halo α,β-unsaturated aldehyde 1 (1
mmol, 1 equiv), nitrile RCH2CN (1.5 mmol, 1.5 equiv), Et3N (0.5
mmol), and CH2Cl2 (8 mL) was stirred for 15–30 min at r.t. until the
reaction was complete (TLC). The mixture was then poured into H2O
(20 mL) and extracted with CH2Cl2 (3 × 10 mL). The organic phases
were combined, washed with H2O (2 × 10 mL), dried (Na2SO4), and
concentrated to give the crude Knoevenagel adduct, which was used
directly in the synthesis of the corresponding 2-aminopyridine.
Anal. Calcd for C24H25N3O2: C, 74.39; H, 6.50; N, 10.84. Found: C,
74.44; H, 6.49; N, 10.88.
(6aS,11aS)-8-Amino-2-methoxy-6a-methyl-
5,6,6a,11,11a,11b,12,13-octahydro-4bH-naphtho[2′,1′:4,5]inde-
no[1,2-b]pyridine-9-carbonitrile (3d)
White solid; yield: 291 mg (81%); mp 267–268 °C; Rf = 0.5 (20%
2-Aminopyridines 3; General Procedure with Microwave Heating
EtOAc–hexanes).
A mixture of Knoevenagel adduct 2 (~1 mmol, 1 equiv) and NH4OAc (3
mmol, 3 equiv) in DMF (4 mL) was irradiated in the closed vessel of
the microwave reactor at 130 W, 140 °C, and 8 bar for 5 min. The mix-
ture was then cooled, poured into ice-cold H2O (20 mL), and extracted
with EtOAc (3 × 20 mL). The organic portion was washed with H2O
(2 × 10 mL), dried (Na2SO4), and concentrated. The crude product was
purified by column chromatography (silica gel, 20% EtOAc–hexanes).
IR (CHCl3): 3396, 3324, 3188, 2924, 2851, 2214, 1652, 1500, 1424,
772 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.54 (s, 1 H), 7.23 (d, J = 8.6 Hz, 1 H),
6.73 (dd, J1 = 2.5, J2 = 8.5 Hz, 1 H), 6.65 (d, J = 2.3 Hz, 1 H), 5.42 (s, 2 H),
3.79 (s, 3 H), 1.59–2.98 (m, 13 H), 0.99 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 177.5, 159.2, 157.6, 137.7, 137.0, 132.2,
126.2, 125.7, 117.6, 113.9, 111.6, 87.6, 55.2, 54.7, 46.6, 44.3, 37.6,
33.2, 29.7, 29.1, 27.4, 26.2, 17.3.
2-Aminopyridines 3; General Procedure with Conventional Heat-
ing
LC/MS (ESI): m/z = 359 [M+].
Anal. Calcd for C23H25N3O: C, 76.85; H, 7.01; N, 11.69. Found: C, 76.80;
H, 7.07; N, 11.66.
A mixture of Knoevenagel adduct 2 (~1 mmol, 1 equiv) and NH4OAc (3
mmol, 3 equiv) in DMF (4 mL) was stirred at 120 °C for 5 h. The mix-
ture was cooled, poured into ice-cold H2O (20 mL), and extracted with
EtOAc (3 × 20 mL). The organic portion was washed with H2O (2 × 10
mL), dried (Na2SO4), and concentrated. The crude product was puri-
fied by column chromatography (silica gel, 20% EtOAc–hexanes).
(4aR,4bS,6aS,11aS,11bR)-8-Amino-2-bromo-4a,6a-dimethyl-
4,4a,4b,5,6,6a,11,11a,11b,12-decahydro-1H-naphtho[2′,1′:4,5]in-
deno[1,2-b]pyridine-9-carbonitrile (3e)
White solid; yield: 326 mg (77%); mp 247–248 °C; Rf = 0.4 (20%
EtOAc–hexanes).
(2S,4aR,4bS,6aS,11aS,11bR)-8-Amino-9-cyano-4a,6a-dimethyl-
2,3,4,4a,4b,5,6,6a,11,11a,11b,12-dodecahydro-1H-naph-
tho[2′,1′:4,5]indeno[1,2-b]pyridin-2-yl Acetate (3a)
IR (CHCl3): 3398, 3331, 3195, 2923, 2852, 2215, 1554, 1423, 1247,
1033 cm–1
.
White solid; yield: 336 mg (83%); mp 248–250 °C; Rf = 0.4 (20%
EtOAc–hexanes).
1H NMR (300 MHz, CDCl3): δ = 7.50 (s, 1 H), 6.30 (s, 1 H), 5.43 (s, 1 H),
5.3 (br s, 2 H), 1.10–2.12 (m, 15 H), 1.03 (s, 3 H), 0.99 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 176.9, 159.1, 141.5, 137.5, 130.9, 125.5,
123.5, 121.0, 117.3, 87.7, 55.6, 48.3, 46.3, 35.3, 34.6, 33.0, 31.0, 30.5,
29.7, 29.2, 20.5, 18.8, 17.0.
IR (CHCl3): 3347, 3217, 2941, 2854, 2213, 1731, 1556, 1247, 1031,
756 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1905–1912