Synthesis and structure of new N-bromobenzyl bis-quinolizidine derivatives

Article abstract of DOI:10.2174/157017812802139672

New potentially biologically active N-bromobenzyl derivatives of α-isosparteine and 2-methylsparteine were obtained. Newly obtained compounds were characterized by IR and NMR spectroscopy. The structure of the new compounds in solution was proposed.

Full text of DOI:10.2174/157017812802139672

474
Letters in Organic Chemistry, 2012, 9, 474-477
Synthesis and Structure of New N-Bromobenzyl Bis-quinolizidine
Derivatives
Beata Jasiewicz*, Karolina Malczewska-Jaskóꢀa and Katarzyna Poꢀom
Faculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6, 60-780 Poznaꢀ, Poland
Received January 26, 2012: Revised May 10, 2012: Accepted May 10, 2012
Abstract: New potentially biologically active N-bromobenzyl derivatives of ꢁ-isosparteine and 2-methylsparteine were
obtained. Newly obtained compounds were characterized by IR and NMR spectroscopy. The structure of the new com-
pounds in solution was proposed.
Keywords: Bromobenzyl derivatives, IR and NMR spectroscopy, sparteine derivatives, sparteine stereoisomers.
INTRODUCTION
oxosparteine [7]. As the object of our research we chose con-
formationally stable ꢀ-isosparteine (1) and conformationally
flexible 2-metylsparteine (2).
Quinolizidine alkaloids make one of the most abundant
groups of alkaloids distributed within the Leguminosae. It is
known that bis-quinolizidine alkaloids are characterized and
distinguished by their valuable pharmacological properties as
they show antihypersensitive, antiinflammatory, antidepres-
sant, antiarrhythmic, diuretic and hypoglicemic activity [1-
5]. It has been found that chemical modification of bis-
quinolizidine molecules can strongly influence their potential
biological activity.
Of the sparteine diastereoisomers, ꢀ-isosparteine is prac-
tically conformationally homogeneous with the most stable
trans-trans full-chair conformer whereas, the skeleton of 2-
methylsparteine (similarly as sparteine) is very flexible, so
sparteine and its derivatives can assume a conformation with
ring C either a boat (the boat conformer) or a chair (the chair
conformer), or occur in conformational equilibrium (Scheme
1).
A/B
C/D
C/D
A/B
C/D
A/B
8
8
8
9
7
14
17
7
6
15
17
N
6
7
17
16
12
6
11
12
5
2
11
9
5
10
9
13
5
10
4
11
N 1
16 N
10
N
16
4
15
N 1
13
4
N 1
2
13
2
12
CH3
3
14
15
CH3
3
3
14
trans-trans
trans - trans
ꢀ-isosparteine
trans-cis
2-methylsparteine
Scheme 1. The conformational-configurational arrangements and atom numbering of ꢀ-isosparteine and 2-methylsparteine.
As a continuation of our studies aimed at the determina-
tion of the influence of a substituent introduced to a bis-
quinolizidine molecule on the stereochemistry, and proper-
ties of this system we obtained new potentially biologically
active N-bromobenzyl-substituted bis-quinolizidine deriva-
tives. The preparation and X-ray crystallographic analysis of
the benzyl quaternary salt of sparteine were described earlier
by Yoshizawa and co-workers [6]. Gadepalli and co-workers
describe the synthesis and X-ray analysis of (+)-6-benzyl-17-
RESULTS AND DISCUSSION
Treatment of ꢀ-isosparteine (or 2-methylsparteine) with
3 equivalents of o-(m-, p-)bromobenzyl bromides in MeOH
afforded the N16-o-(m-, p-)bromobenzyl-ꢀ-isosparteinium
(or 2-methylsparteinium) bromide (Scheme 2).
The yields of the reactions 2-methylsparteine with o-(m-,
p-)bromobenzyl bromides are almost the same (74-78%),
while the yields of the reactions of ꢁ-isosparteine with o-(m-,
p-)bromobenzyl bromides depend on the position of bromine
atom in aromatic ring. This fact is connected with all-chair
structure of the alkaloid.
*Address correspondence to this author at the Faculty of Chemistry, Adam
Mickiewicz University, Grunwaldzka 6, 60-780 Poznaꢂ, Poland; Tel: +48-
61-829-1354; Fax: +48-61-829-1505; E-mail: beatakoz@amu.edu.pl
1875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

Synthesis and Structure of New N-Bromobenzyl Bis-quinolizidine
Letters in Organic Chemistry, 2012, Vol. 9, No. 7
475
Br
Br-
N
Br
N
N
N
CH2Br
R
R
R = H for 1
R = CH3 for 2
Br
Br
-o for 6
-m for 7
-p
-o for 3
-m for 4
-p for 5
R = CH3
R = H
for 8 ꢀ
Scheme 2.
All compounds were characterized on the basis of spec-
tral studies. Their structures were determined by comparison
of their spectral data with those of ꢀ-isosparteine and 2-
methylsparteine. The IR spectra of quinolizidine alkaloids
have the characteristic so-called “trans-band” region (T-
band, 2840-2600 cm-1). The “trans-band” region in the spec-
trum of the ꢀ-isosparteine comprises three main absorption
maxima at about 2793, 2758 and 2735 cm-1 [8], which result
from the fact that the axial hydrogen atoms at C2, C6, C10
and C11, C15, C17 are in position trans in relation to the
lone pairs on the nitrogen atoms at the N1 and N16. The at-
tachment of a bromobenzyl group to one nitrogen atom
changes the type and intensity of the trans band complex –
only one absorption band is present near 2800 cm-1. The T-
band of 2-methylsparteine consists of one maximum near
2790 cm-1 [9]. IR spectrum of 2 in CDCl3 solution shows
within the 2200-2100 cm-1 region an additional band arising
from C-D stretching vibration of CDCl3 molecule associated
with the nitrogen atom N16. The appearance of this band
with p-bromobenzyl substituent (compounds 5 and 8, respec-
tively).
13C chemical shifts for C2, C3, C5, C6, C7 and C10 car-
bon atoms of N16-bromobenzyl-2-methylsparteinium salts
approximate the analogous values of 2-methylsparteine (Ta-
ble 1). This result corroborates the presence of chemically
unchanged A and B rings preserving the trans-quinolizidine
form in N16-bromobenzyl salts. The deshielding influence of
the benzyl substituent on N16 nitrogen of the alkaloid con-
sidered causes a down-field shift of the signals assigned to ꢀ
carbons, i.e. C11, C15, C17 as compared with the respective
2-methylsparteine ꢁC values. The change in the chemical
shift of the carbon atom C13 by over 8 ppm testifies to the
boat-chair conformation of C/D rings with cis fusion. The
position of a bridge carbon signal C8 is diagnostic of the
conformation of the two fused B/C rings in the sparteine
skeleton. According to the criterion of Bohlmann and Zeis-
berg for the one carbon bridge in the bicyclo[3.3.1] moiety,
this resonance is expected to move downfield in the se-
quence boat/boat, chair/boat, chair/chair [10,11]. For 2-
methylsparteine (chair/boat) this resonance occurs at about
27.5 ppm (theor. 26.1 ppm); for ꢀ-isosparteine (chair/chair)
at 36.4 ppm (theor. 35.4 ppm) [11]. These values are in
agreement with the values obtained for N-bromobenzyl de-
rivatives: 28.8 ppm for 2-methylsparteinium salts and 33.2
ppm for ꢀ-isosparteinium salts.
supports the claim that in solution ring
C of 2-
methylsparteine exists in boat conformation, which is
equivalent to a “transoidal” arrangement of N1 and N16. The
attachment of a bromobenzyl group to the N16 results in the
disappearance of the absorption at 2790 cm-1 and appearance
of a new absorption band at 2815 cm-1. Also the absorption
band assigned to the interaction of nitrogen atom N16 with
CDCl3 molecule disappears. The IR spectra of all new com-
pounds show additional bands characteristic of bromobenzyl
substituents.
The set of eight signals assigned to the alkaloid in the 13C
NMR spectra of 3-5 is correctly reproduced by the symmet-
ric structure of ꢀ-isosparteine. Additional signals assigned to
the bromobenzyl are observed at: 63.7 ppm (-CH2) and
122.0-140.0 ppm (aromatic ring). The presence of a bro-
mobenzyl substituent has practically no influence on the
change in the chemical shifts of carbon atoms ꢀ-isosparteine.
The only differences in the NMR spectra of compounds 3-5
appear in the region corresponding to the benzyl group sub-
stituted with a bromine atom at -ortho, -metha, and -para
positions. Similarly, the differences in the NMR spectra of
compounds 6-8 are also related to different substitution of
benzyl group. Therefore, Table 1 presents the chemical shift
of carbon and hydrogen atoms in the spectra of the represen-
tative derivatives of ꢀ-isosparteine and 2-methylsparteine
The assignments of the 1H NMR signals to particular pro-
tons were achieved by two-dimensional methods, 1H-13C
HETCOR and 1H-1H COSY.
The signals of protons connected with the C11, C15 and
C17 carbons appear within the range 3.70 > ꢁH > 3.00 ppm.
A characteristic singlet appearing in the range 4.60-4.70 ppm
was assigned to the aliphatic protons in the benzyl moiety
attached to the nitrogen atom. The signals from aromatic
protons are in the range 7.0 – 8.0 ppm.
EXPERIMENTAL SECTION
General Techniques
The IR spectra were recorded by means of a FT-IR
Bruker 113v spectrometer (CDCl3 solution). The 1H and 13C
NMR spectra were measured on a Varian Gemini 300 spec-

476 Letters in Organic Chemistry, 2012, Vol. 9, No. 7
Jasiewicz et al.
Table 1. NMR Spectroscopic Data of ꢀ-isosparteine, 2-methylsparteine and their Bromobenzyl Derivatives 5 and 8 (in CDCl3)
ꢀ-isosparteine (1)
N-p-bromobenzyl-
ꢀ-isosparteine (5)
N16-p-bromobenzyl-
-2-methylsparteine (8)
2-methylsparteine (2) [13]
Carbon
Atom
[12]
ꢁC
ꢁH
ꢁC
ꢁH
ꢁC
ꢁH
ꢁC
ꢁH
1.72
2.70
1.70
2.65
2
3
4
5
57.2
56.5
58.0
1.89
57,5
34,3
23,3
30,1
2.08
1.63
1.48
1.65
1.50
1.51
1.21
1.30
1.50
25.3
24.9
30.0
25.2
24.8
29.3
35.3
24.5
30.2
1.23
1.71
1.20
1.80
1.64
1.64
1.65
1.30
1.59
1.24
1.60
1.65
1.25
2.08
1.35
1.35
6
7
66.3
35.6
1.89
1.45
66.2
33.7
1.95
1.45
66.2
33.8
1.74
1.85
66,4
33,7
1.90
1.95
1.52
1.52
1.50
1.50
1.10
2.11
1.50
2.30
8
36.4
35.6
55.8
66.3
30.0
33.2
33.7
55.9
66.2
29.3
27.5
36.4
57.3
64.4
34.7
28,8
33,7
56,7
73,6
26,4
9
1.45
1.85
1.54
1.95
1.99
2.90
2.00
2.85
1.70
2.93
1.85
2.93
10
11
12
1.89
3.00
2.03
3.10
1.59
1.24
1.60
1.30
1.42
1.53
2.70
1.45
1.23
1.71
1.25
1.70
1.32
1.66
1.35
1.65
13
14
15
17
24.9
25.3
57.2
55.8
24.8
25.2
56.5
55.9
24.9
26.0
55.3
53.5
16,2
22,9
65,0
61,7
1.63
1.48
1.60
1.50
1.48
1.63
2.45
1.55
1.72
2.70
3.35
3.15
1.61
2.78
3.65
3.15
1.89
2.90
3.60
3.45
2.35
2.68
3.70
3.40
-CH2
-
-
-
-
-
-
-
-
-
-
-
-
63.7
-
4.65
-
63.7
20.7
4.65
1.05
-
-CH3
-
-
21.3
1.01
a
b
c
d
134.9
128.6
131.3
120.8
-
-
-
-
-
-
-
-
135.5
128.6
131.6
121.3
7.24
7.14
-
7.57
7.29
-
a
b
c
b
c
d
Br
ꢀ
trometer at 300.13 and 75.462 MHz, respectively and at am-
bient temperature, using ~0.5 M solution in CDCl3, TMS as
internal reference. Elemental analysis was carried out by
means of a Perkin-Elmer 2400 CHN automatic device.
General procedure for preparation of N-bromobenzyl
bis-quinolizidines
To a methanol solution consisting of 1 mmol of the alka-
loid [1 (234 mg) or 2 (248 mg)] o-(m-, p-)bromobenzyl bro-
mide (747 mg; 3 mmol) was added. The reaction mixture
was stirred at room temperature. Completion of the reaction
was controlled by TLC examination [MeOH:(CH3)2
2-Methylsparteine was obtained by the reaction of 2-
oxosparteine with methyllithium [9]. ꢀ-Isosparteine was ob-
tained according to literature [14].

Synthesis and Structure of New N-Bromobenzyl Bis-quinolizidine
Letters in Organic Chemistry, 2012, Vol. 9, No. 7
477
CO:NH4OH 1:1:0.5 v/v). Then half of the solvent volume
was evaporated under vacuum and 5 ml of acetone was
added. The oils obtained were dried under pressure in a des-
iccator above P2O5.
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ACKNOWLEDGEMENTS
Declared none.
CONFLICT OF INTEREST
The author(s) confirm that this article content has no con-
flicts of interest.