Nov-Dec 2007
Synthesis and Characterization of Some Lupinine Derivatives
1343
0.021 mol in absolute benzene 20 ml was added dropwise during
30 min. The reaction mixture was stirred at 70-75 °C for 4-5 h.
After cooling the triethylamine hydrochloride precipitated and
was filtered off and washed with benzene. The filtrate was
evaporated in vacuum. The raw product was purified by column
chromatography (Al2O3, eluent benzene-chloroform-ethanol
18:15:1).
producing readily the fragment ion m/z 150 (see Scheme
2). Also two other fragment ions from m/z 359, namely
m/z 331 and m/z 248 were verified calculationally.
EXPERIMENTAL
But-2-enoic acid octahydro-quinolizin-1-ylmethyl ester
(3a). The compound was prepared according to the general
method, yield 3.32 g (79 %); Rf= 0.66 (chloroform-ethanol 2:1);
1H NMR (D2O): ꢀ= 1.38-2.32 (14H); 2.86 (2H); 3.98-4.36 (2H);
5.88 (1H), 7.03 (1H); MS (ESI): calcd. for C14H24N1O2 [M+H]+
= 238.18016. Found [M+H]+ = 238,18008. Diff. 8.0 ꢀ 10-5. Anal.
Calcd. for C14H23N1O2: C, 70.76; H, 9.68; N, 5.89. Found C,
70.42 H, 9.33; N, 6.0.
Mass Spectrometry. Electrospray ionization (ESI) mass
spectra were measured using a Fourier transform ion cyclotron
resonance mass spectrometer (Bruker BioApex 47e, Bruker
Daltonics, Billerica, USA), equipped with a 4.7 Tesla, 160 mm
bore superconducting magnet (Magnex Scientific Ltd.,
Abingdon, UK), InfinityTM cell and interfaced to an electrospray
ionization source (Bruker Apollo ESI source). The instrument
was calibrated externally using a water:acetonitrile solution of
sodium trifluoroacetate, as introduced by Moini et. al. [10]. The
sample solution was continuously introduced into the interface
sprayer by a syringe infusion pump at a flow rate of 50 μl/h
under atmospheric pressure. The compounds were first dissolved
into ethanol at a concentration of 1 mg/mL. These solutions
were diluted with 100:1 methanol:acetic acid solution to the
final concentration of 5 μM. In collision-induced dissociation
(CID) experiments, collisionally cooled precursor ions were
isolated in the ICR cell by the CHEF isolation technique [11].
The ions were excited and allowed to undergo collisions with
pulsed argon gas, and after dissociation delay time the spectrum
was collected.
2-Methyl-benzoic acid octahydro-quinolizin-1-ylmethyl
ester (3b). The compound was prepared according to the general
method, yield 4.88 g (85 %); Rf= 0.80 (chloroform-ethanol 2:1);
1
mp. 32-34 °C; H NMR (MeOD): ꢀ= 1.50-2.07 (14H); 2.58
(3H); 3.04 (2H); 4.24-4.63 (2H); 7.27-7.32 (2H); 7.44 (1H);
7.88-7.90 (1H); MS (ESI): calcd. for C18H26N1O2 [M+H]+
=
288.19581. Found [M+H]+ = 288.19548. Diff. 3.3 ꢀ 10-4. Anal.
Calcd. for C18H25N1O2: C, 75.15; H, 8.69; N, 4.86. Found C,
75.34; H, 8.94; N, 4.86.
General procedure for preparation of the amides (4a and
4b). A mixture of aminolupinine 3.36 g (0.02 mol), triethyl-
amine 2,5 g and absolute ether 80 ml was cooled to 0 °C. Acid
chloride 3.1 g (0.021 mol) in absolute benzene 20 ml was added
dropwise during 1 h. The reaction mixture was refluxed for 3 h.
After cooling the triethylamine hydrochloride precipitated and
was filtered off and washed with ether. The filtrate was
evaporated in vacuum. The raw product was purified by column
chromatography (SiO2, eluent chloroform:ethanol 2:1).
Crystallographic data. Compound 6 were collected by on a
Nonius Kappa CCD diffractometer using graphite-monochro-
mated Mo-Kꢀradiation (ꢁ = 0.71073 Å). The intensity data were
corrected for Lorenz and polarization effects, and an empirical
absorption correction was applied to the net intensities. The
structure was solved by direct methods using SHELXS-97 [12]
and refined using SHELXL-97 [13].
2-Methyl-N-(octahydro-quinolizin-1-ylmethyl)-benzamide
(4a). The compound was prepared according to the general
method, yield 4.58 g (80 %); Rf= 0.62 (chloroform-ethanol 2:1);
Crystallographic summary: C19H26N2S, Mr
=
312.46,
Monoclinic, P21, a = 8.5101(2), b = 10.5297(2), c = 9.8836(2), ꢂ
= 114.034(1), V = 808.87(3), Z = 2, Dc = 1.283 g/cm3, μ = 0.199
mm-1, Flack ꢃ parameter = -0.04(4), F(000) = 336, T = 120 K,
conventional R(F) = 0.0265 for 3503 unique reflections I >
2ꢄ(I) and wR(F2) = 0.0675 for all 3648 unique data.
1
mp. 119-120 °C; H NMR (CDCl3): ꢀ= 1.25-2.09 (14H); 2.48
(3H); 2.80 (2H); 3.56-3.72 (2H); 7.16-7.38 (4H); MS (ESI):
calcd. for C18H27N2O [M+H]+ = 287.21179. Found [M+H]+ =
287.21188. Diff. 9.0 ꢀ 10-5. Anal. Calcd. for C18H26N2O: C,
75.41; H, 9.08; N, 9.77. Found C, 75.13; H, 9.22; N, 10.11.
2-Benzoyl-N-(octahydro-quinolizin-1-ylmethyl)-benzamide
(4b). The compound was prepared according to the general
method, yield 3.6 g (68.6 %); Rf= 0.62 (chloroform-ethanol 2:1);
1H NMR (CDCl3): ꢀ= 1.25-1.96 (14H); 2.85 (2H); 3.60-3.79
(2H); 7.30-7.62 (9H); MS (ESI): calcd. for C24H30N2O2 [M+H]+
= 377.22236. Found [M+H]+ = 377.22219. Diff. 1.7 ꢀ 10-4. Anal.
Calcd. for C24H29N3O2: C, 73.6; H, 7.4; N, 10.4. Found C, 73.4;
H, 7.0; N, 10.0.
Computational method. Ab initio and hybrid density
functional (DFT) calculations were performed with the
Gaussian03 [14] series of programs on Sun Fire 25K hardware
on the Center for Scientific Computing (CSC) in Espoo and on
Intel Pentium 4 Xeon hardware at the University of Joensuu.
First, different conformations for both the neutral and different
protonated molecules (3a, 4a and 4b) were calculated employing
a Hartree-Fock (HF) procedure using the 3-21G basis set. Final
optimized geometries were obtained using the density functional
calculations (DFT) at the B3LYP/6-31G(d) level of theory.
Harmonic frequency analysis was done also using the B3LYP/6-
31G(d) basis set and the structures correspond to the true
equilibrium configuration as no imaginary frequencies were
obtained. The visualization of structures was performed with
GaussView 3.0.[15]
1H NMR spectra were recorded on a Bruker Avance 250
NMR spectrometer.
The starting lupinine was isolated from commercial grade
anabasine sulphate [1]
General procedure for preparation of the esters (3a and
3b). A mixture of lupinine 3.4 g (0.02 mol), triethylamine 2,5 g
and absolute benzene 80 ml was cooled to 0 °C. Acid chloride
8-(Octahydro-quinolizin-4-ylmethylsulfanyl)-quinoline (6).
The suspension of 8-mercaptoquinoline, sodium and benzene
was heated to reflux and bromolupinine (5) was added. The
reaction mixture was heated for 6 h. After the reaction sodium
bromide precipitated and was filtered off. Benzene 100 ml was
added to the filtrate and washed few times with 10 % NaOH
solution. The organic phase was dried over Na2SO4. The solvent
was evaporated on vacuum resulting oil which turned into
colorless crystals during the storage. The product was
recrystallized from acetone. Yield 2.81 g (45 %); Rf= 0.39
1
(chloroform-ethanol 2:1); mp. 111-112 °C; H NMR (CDCl3):
ꢀ= 1.48-2.02 (14H); 2.89 (2H); 3.20-3.34 (2H); 7.41-7.55 (4H);
8.10-8.13 (1H); 8.93-8.95 (1H); MS (ESI): calcd. for C19H25N2S
Tlegenov, Rust T.
