Conversion of 10-bromo-10,11-dihydrocinchonidine into 8-oxa-1-azabicyclo[4. 3.0]nonane derivatives and related compounds: A structural study

Article abstract of DOI:10.1016/j.molstruc.2004.05.031

The structure of dehydrobromination products of 10-bromo-10,11- dihydrocinchonidine 2c has been investigated in order to explore the scope of the conversions so far observed for quinine and cinchonine. The 2c rearranges into a mixture of 4(S)-(E-propenyl)-6(S),7(R)-(quinol-4-yl)-8-oxa-1(R)- azabicyclo[4.3.0]nonane 6 and its Z-propenyl diastereomer 8 in the ratio 3: 1 and also provides Z-3,10-didehydro-10,11-dihydrocinchonidine 18. The mixture of 6 and 8 undergoes catalytic hydrogenation giving 4(S)-propylo-6(S),7(R)-(quinol- 4-yl)-8-oxa-1(R)-azabicyclo[4.3.0]nonane 10. On treatment with an acid the alkaloid 6 yields [4(S)-E-propenyl-2(S)-piperidinyl]-4-quinoline α(R)-methanol 14. Its side chain undergoes hydrogenation affording 4(S)-propylo-derivative 12 which also forms on treatment of 10 by acid. The alkaloids 6, 8, 10, 12 and 14 appear as dominating conformers in their equilibrium mixtures.

Full text of DOI:10.1016/j.molstruc.2004.05.031

Journal of Molecular Structure 705 (2004) 167–176
www.elsevier.com/locate/molstruc
Conversion of 10-bromo-10,11-dihydrocinchonidine
into 8-oxa-1-azabicyclo[4.3.0]nonane derivatives
and related compounds: a structural study
*,1
Danuta Desperak, Jacek Pawłowski, Jacek Thiel
Faculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6, PL 60-780 Pozna n´ , Poland
Received 22 April 2004; revised 28 May 2004; accepted 28 May 2004
Abstract
The structure of dehydrobromination products of 10-bromo-10,11-dihydrocinchonidine 2c has been investigated in order to explore the
scope of the conversions so far observed for quinine and cinchonine. The 2c rearranges into a mixture of 4(S)-(E-propenyl)-
6
(S),7(R)-(quinol-4-yl)-8-oxa-1(R)-azabicyclo[4.3.0]nonane 6 and its Z-propenyl diastereomer 8 in the ratio 3: 1 and also provides
Z-3,10-didehydro-10,11-dihydrocinchonidine 18. The mixture of 6 and 8 undergoes catalytic hydrogenation giving 4(S)-propylo-6(S),7(R)-
quinol-4-yl)-8-oxa-1(R)-azabicyclo[4.3.0]nonane 10. On treatment with an acid the alkaloid 6 yields [4(S)-E-propenyl-2(S)-piperidinyl]-4-
quinoline a(R)-methanol 14. Its side chain undergoes hydrogenation affording 4(S)-propylo-derivative 12 which also forms on treatment of
0 by acid. The alkaloids 6, 8, 10, 12 and 14 appear as dominating conformers in their equilibrium mixtures.
(
1
q 2004 Elsevier B.V. All rights reserved.
Keywords: Cinchona alkaloids; Rearrangement; Dehydrobromination; Conformational equilibria; NMR spectroscopy
1
. Introduction
was accompanied by the ‘cage-conserved’ alkaloids with
C-9 OMs groups substituted by the nucleophiles [4].
Hoffmann and collaborators also transformed the
cinchona vinyl side chain into the ethynyl one.
The obtained 10.11-didehydrocinchona alkaloids were
further functionalized to provide Z-halovinyl-, propynol-,
propyne-nitryl- and allene-derivatives [5]. Cook with
coworkers synthesized 10(R)- and 10(S),11-dihydroxydi-
hydroquinine via the Sharpless catalytic asymmetric
dihydroxylation [6].
Recent studies on Cinchona alkaloids, not to mention
the first entirely stereoselective total synthesis of quinine
1], continue to reveal new facts concerning their
[
chemistry. For example, Hoffmann and coworkers
found that during acidic hydrolysis of quinine and
quinidine mesylates inversion of configuration at C9
took place whereas configuration at C9 was retained for
the same derivatives of epiquinine and epiquinidine after
similar treatment [2]. This research group also reported
on ‘the first and second Cinchona rearrangement’.
The first one was achieved by conversion of 9-halo-
New rearrangement of 10-bromo-10,11-dihydroquinine
[7] and 10-bromo-10,11-dihyrocinchonine [8] into the
8-oxa-1-azabicyclo[4.3.0]nonane derivatives has been
described. A question whether the scope of this reaction
extends on the remaining Cinchona alkaloids, prompted us
to investigate the so far unexplored cinchonidine.
[
3] or 9-mesyl-derivatives [4] into 1-azabicyclo[3.2.2]
nonane derivatives a-functionalized relative to the
bridgehead nitrogen. The second ‘cage-expanded’
reaction afforded b-functionalized 1-azabicyclo[3.2.2]no-
nanes by displacement of C-9 cinchona mesilates with
various nucleophiles [4]. Formation of these products
2. Experimental
*
Corresponding author. Tel.: þ48-61-8291310; fax: þ48-61-8658008.
E-mail address: boczon@amu.edu.pl (J. Thiel).
On retirement from Faculty of Chemistry, Adam Mickiewicz
General. Commercial cinchonidine was used as starting
material after prior separation of 10,11-dihydrocinchonidine
by means of mercuric acetate process [9]. Melting points are
1
University.
0022-2860/$ - see front matter q 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2004.05.031

168
D. Desperak et al. / Journal of Molecular Structure 705 (2004) 167–176
uncorrected. Optical rotations were measured on a Perkin–
Elmer 243 b Polarimeter. The IR spectra were recorded
using FT-IR–Raman Nicolette 760 and Ft-IR Brucker IFS
yielded: 3.16 g (alkaloids A þ D; only 6 and 8 detected by
NMR), 0.23 g (A þ B þ C þ D), 0.84 g (D).
The NMR data for 6 and 8: see Table 1.
1
13v spectrometers. NMR spectra were obtained on a
Varian Gemini BB and Varian Mercury spectrometers
at observation frequencies 75 and 300 MHz. The
NMR assignments were made by first-order analysis of
2.3. 4(S)-propylo-6(S),7(R)-(quinol-4-yl)-8-
oxa-1(R)-azabicyclo[4.3.0]nonane 10
1
1
1
the H resonances and aided by DEPT, H– H- and
1
A mixture of 6 and 8 (1.54 g) from the above 3.16 g
fraction was dissolved in 99.8% ethanol (60 ml) and
hydrogenated by shaking with Adams catalyst (PtO2,
3
1
C– H-cosy as well as NOESY spectra. MS spectra
were performed on a AMD 402 instrument (AMD-INTEC-
TRA Germany). Microanalyses were performed on a Euro
EA-2000 (Euro-Vector) apparatus.
0
.253 g) under hydrogen (4–4.5 atm) at room temperature
for 4 h. The catalyst was then removed by filtration.
The filtrate showed three spots on TLC (see Section 2.2)
marked X, Y, Z in accordance with decreasing R values.
2
.1. 10-Bromo-10,11-dihydrocinchonidine 2c
f
The solvent was removed from the filtrate by evaporation
under reduced pressure to give 1.035 g of the crude product.
Column chromatography (150 g of neutral alumina-Aldrich
partially deactivated by treatment with water 9 ml; benzene
122 ml; 0.5% (v/v) (122 ml); 1% (v/v) (122 ml); 2% (v/v)
(540 ml) and 3.5% (v/v) (122 ml) of 99.8% ethanol in
benzene; 540 ml of methanol) yielded: 0.158 g pure 10
(by NMR; TLC showed X þ Z); 0.459 g (X þ Y þ Z);
0.098 g (Y, unidentified over-reduction product making
Cinchonidine dihydrobromide (1c·2HBr·2H O, 16.72 g)
2
was added in portions to 62% hydrobromic acid (84 ml)
keeping the temperature below 5 8C. The obtained solution
was then left in a stoppered flask for 73 h at room
temperature. The reaction mixture was poured onto ice
(
,190 g) and treated with 57 g of K CO . The obtained still
2
3
acidic liquid was added gradually on cooling to 50 ml of 25%
aqueous ammonia: 50 ml of water. The precipitated 2c
was immediately filtered off, washed with water till
disappearance of alkaline reaction, air dried for 24 h and
then dried at 100 8C for 1 h. The yield was 12.04 g (94.4%).
Analysis calculated for C H N OBr (375.31): C 60.81; H
1
,15%—by H NMR—of the total crude product); 0.200 g
(Y þ Z, decomposition products of 10 and Y).
Data for 10: mp 71–74 8C (cryst. from CDCl ,
3
non-crystallizing from other solvents), ½aŠ ¼ 2143:78
1
9
23
2
d
(
c ¼ 1:000; ethanol).
þ
6
.18; N 7.46; found: C 60.10; H 6.14; N 7.27%.
þ
þ
MS m=z 376.1 (M , 2.27), 374.1 (M , 1.95), 296.2(21.23),
95.2(100), 294.2(24.97), 213.1(9.64), 159.1(22.30),
42.1(12.91), 137.2(73.37), 130.1(42.10), 122.1(21.32),
1.1(19.40), 77.1(20.52), 69.1(44.51), 56.0(43.10).
MS m=z; 296 (M , 0.78), 140(14.67), 139(100),
29(12.18), 97(26.90), 96(33.94), 82(4.76), 69(11.21).
1
HRMS calculated for C H N O, 296.18887; found
2
1
8
19 24
2
2
96.18882.
2
1
IR (KBr; cm ): 3061 (aromatic nC–H); 2966, 2950,
928, 2890, 2859 (aliphatic nC–H); 1590, 1568, 1508, 1450
quinoline nCyC), 1463, 1357 (aliphatic dC–H), 1245, 1122,
2
2
1
.2. 4(S)-(E-propenyl)-6(S),7(R)-(quinol-4-yl)-8-oxa-
(R)-azabicyclo[4.3.0]nonane 6 and 4(S)-
(Z-propenyl)-6(S),7(R)-(quinol-4-yl)-8-
oxa-1(R)-azabicyclo[4.3.0]nonane 8
(
1
2
4
056ðn
Þ; 983, 930, 761.
C–O–C
NMR: see Table 1.
.4. Reaction of 10 with hydrochloric acid
To a solution of NaHCO (2.27 g) in water (202 ml),
3
2
c (10.08 g) and 99.7% ethanol (806 ml) were added and the
Dimedone (1 g) dissolved in water (80 ml) and 5 ml of
N HCl were added to the solution of 10 (120 mg) in 99.7%
mixture was refluxed (using water bath) till almost all
the alkaloid is dissolved (up to 18 h; small amounts of the
products B and C may deposit). The obtained liquid showed
on TLC (neutral alumina Merck; benzene: 99.7% ethanol/9:1
v/v) the spots A–D marked in order of increased polarity and
made visible using Dragendorff reagent. Ethanol was
removed in vacuo from the liquid and the remainder was
extracted with diethyl ether (1300 ml). 1.6 g of the alkaloids
B and C precipitated from the extract which was then dried
over KOH in pellets. Additional 1.01 g of B and C deposited
on the KOH. Ether was removed from the dried extract giving
ethanol (10 ml). Crystalline condensation product of CH O
2
with dimedone soon precipitates during heating of the
reaction mixture on the hot water bath.
0
2.4.1. 2,2 -Methylene-di-(5,5-dimethylcyclohexan-
1,3-dione)
The precipitate was filtered off, washed with water and
air dried yielding 72 mg of C H O . Mp: 188–190 8C,
1
7 24 4
(reported [10]: 190–192 8C). MS m=z : 292(100),
272.2(14.49), 233.2(10.27), 208.1(12.97), 191.1(12.00),
180.2(16.33), 166(11.30), 165.1(67.02), 124.1(17.04),
83.1(18.66). HRMS calculated for C H O : 292.16745;
,
(
4.7 g of the alkaloids A–D. Column chromatography
300 g of neutral alumina Aldrich partially deactivated with
water 9 ml; benzene 350 ml; 0.1% (v/v) (1870 ml) and 10%
v/v) (1058 ml) of ethanol in benzene; methanol 1052 ml)
1
7 24 4
(
found 292.16741.

Table 1
3
NMR data (CD Cl/TMS) for the alkaloids 6, 8 and 10
Carbon atom No.
DEPT
6
8
10
Rabe
IUPAC
dC
dH
Splitting
pattern
J (Hz)
dC
dH
Splitting
pattern
J (Hz)
dC
dH
Splitting
pattern
J (Hz)
a
6
5
2
CH
CH
2
2
44.66
2.96
dt
10.9; 4.6; 4.6
10.7; 10.7; 3.3
45.61
3.04
2.66
1.57
1.36
1.99
1.46
1.14
3.44
5.77
4.97
4.35
5.28
ddd
ddd
m
11.1; 7.2; 3.9
11.1; 8.1; 3.2
45.79
29.54
2.96
2.63
1.51
1.23
0.83
1.36
1.20
3.45
5.75
4.94
4.36
0.95
ddd
ddd
dddd
m
11.1;7.5;3.6
2
.54
td
11.1;8.0;3.3
b
b
b
3
29.01
1.63
.48
m
29.64
16.1;8.1;3.8; , 1.0
b
b
b
1
m
dtd
m
13.5; 6.9; 6.9; 3.3
4
7
4
5
CH
CH
33.48
30.97
1.94
1.49
bs
S J , 22
28.62
30.58
S J , 30?
30,33
30.17
m
b
2
2
m
m
ddd
m
13.7;7.1;4.7
b
0
.95
ddd
ddd
d(d?)
d
13.3; 9.3; 4.2
ddd
td
13.6; 7.5; 4.6
7.8; 7.8; 4.6
8.2; ?
8
9
2
6
7
9
CH
CH
CH
60.43
76.81
86.82
3.24
5.84
4.98
9.3; 8.1; 3.3
60.43
76.41
87.06
60.72
76.36
87.04
ddd
d
13.7;7.1;4.7
7.8; ?
d(d?)
d
8.2
3.8
4.1
2.7
4.1
d
4
.23
d
2.7
d
3.8
d
0
0
0
0
0
b
c
b
b
b
b
3
1
CH
CH
133.43
124.91
5.38
ddq
15.3; 6.5; 1.6; 1.6; 1.6
132.67
124.05
m
35.76
19.74
m
1
.07
0.77
.90
m
b
c
10
2
5.21
dqd
15.4; 6.5; 6.5; 6.5; 1.5
5.24
m
m
0
m
0
0
0
0
0
1
2
3
4
9
5
6
7
8
1
1
3
2
3
4
CH
CH
CH
3
17.99
150.29
119.36
147.94
128.96
123.00
126.26
128.88
130.30
146.49
1.61
8.92
7.62
dt
d
6.1; 1.5; 1.5
4.5
12.12
150.29
119.14
147.94
128.96
123.13
126.10
128.88
130.35
146.93
1.00
8.93
7.69
d(t?)
d
5.1; ?
4.9
?
13.75
150.36
119.07
147.10
128.33
123.15
126.14
126.14
130.43
147.99
0.57
8.91
7.67
t
7.0
4.4
4.4
0
d
0
0
0
0
0
0
0
b
dd
4.2; ?
d(d?)
d
4 a
0
5
CH
CH
CH
CH
7.90
7.55
7.71
8.15
dd
8.5; , 1.2
8.1; 6.9; 1.4
8.4; 6.9; 1.5
8.5; , 1.1
7.87
7.54
7.72
8.14
dd
?; 0.9
8.1; 6.9; 1.3
?
7.89
7.56
7.71
8.14
dd
8.4;1.5
0
6
ddd
ddd
dd
ddd
ddd
ddd
dd
8.4;6.7;1.4
8.3;6.8;1.4
8.5;0.8
0
b
7
(ddd?)
d(d?)
0
8
8.0; ?
0
0
0
8 a
a
b
c
For IUPAC numbering see fomula 3, Scheme 1.
13
1
1
1
dH have been taken from C– H- and H– H-cosy spectra.
DEPT: CH
2
.

170
D. Desperak et al. / Journal of Molecular Structure 705 (2004) 167–176
2.4.2. [4(S)-Propyl-2(S)-piperidinyl]-4-quinoline-(aR)-
methanol 12. Dihydronicinquidine. Method A
98 mg of nicinquidine acid oxalate The alkaloid 14 was
liberated from this salt by action of saturated aqueous KOH
onto solution of the oxalate in hydrochloric acid followed by
extraction with diethyl ether (2 £ 56 ml). After drying over
K CO , the combined extracts were evaporated giving
The acidic filtrate remaining after the above separation of
the condensation product was extracted (three times) with
diethyl ether (750 ml) to remove the non-alkaloidal
admixtures. The acidic water layer was made alkaline
with concentrated KOH and exhaustively extracted
2
3
65 mg of 14 slightly contaminated by the Z-propenyl
counterpart. Mp (capillary method): 115–119 8C (recryst.
from acetone), ½aŠ ¼ 278:68 (c ¼ 1:00775; ethanol).
MS m=z : 159(100), 158(30.75), 130(90), 129(27.17),
128(22.70), 124(70.29), 124(24.55), 108.1(18.65),
102.0(15.11), 77.0(16.33), 56.0(49.86). MS FAB: M þ 1
(283.1, 100). Analysis calculated for C H N O (282.387):
(
Dragendorff test) with diethyl ether. The combined extracts
were dried over KOH in pellets. Removal of the solvent
gave 72 mg of slightly contaminated 12.
NMR: see Table 2; other data: see Section 2.7.
The alkaloid 12 was also characterized as its
dihydrochloride salt (see Section 2.7.1).
1
8 22 2
C 76.56; H, 7.85; N, 9.92; found: C 75.85; H, 7.84; N,
.46%.
IR (KBr, cm ): 3600–2400 (broad absorption with
9
2
1
2
.5. Reaction of 6 and 8 with hydrochloric acid
extrema at 3258 and 2663; hydrogen bonded NH and OH
groups); 3057,3032 (aromatic nC–H); 2986, 2939, 2871,
2848 (aliphatic nC–H); 1588, 1569,1508 (quinoline nCyC);
1667 and 970(nC–H and dC–H of trans alkene); 1450
(aliphatic dC–H); 1106ðnC–OÞ:
1
0-Bromo-10,11-dihydrocinchonidine 2c (2.897 g),
NaHCO3 (0.561 g), 99.7% ethanol (200 ml) and water
50 ml) were refluxed (on water bath) until the alkaloid
(
dissolved almost entirely (,18 h). Small amounts of
the remaining precipitate displayed on TLC the spots B
and C out of A–D ones observed in the solution. Ethanol
was evaporated in vacuo from the reaction mixture.
The remainder was treated by the solution of dimedone
NMR: see Table 2.
2.6. Z-3,10-Didehydro-10,11-dihydrocinchonidine 18
(
1.86 g) in water (400 ml) and ethanol (30 ml), acidified by
N HCl (12 ml) and heated on a water bath for 90 min with
The above (Section 2.5.2) 20 mg fraction of 18
(alkaloid C) was spectrally identical with (but less pure
than) another fraction (110 mg) of the alkaloid C. The latter
fraction was isolated in a similar manner from dehydro-
bromination products of 2c (5.82 g) by equimolar sodium
bicarbonate (compare Section 2.2). After crystallization
from benzene the alkaloid 18 showed darkening above
3
occasional stirring. After coming to room temperature, the
condensate C H O was filtered off, washed with water
1
7 24 4
and dried. The yield was 1.027 g (45.5%), mp 189–190 8C,
other data: see Section 2.4.1.
The acidic filtrate from the above separation was eight
times extracted with diethyl ether (450 ml) to remove
non-alkaloidal admixtures. The acidic water layer was
then made alkaline with ,20% KOH and extracted with
diethyl ether (500 ml). The extract was dried over
anhydrous K CO on which some alkaloids B and C
200 8C, mp 236–238 8C (dec.) and ½aŠ ¼ 2126:718
d
(c ¼ 0:2325; ethanol).
þ
MS m=z : 294.3 (M , 58.12), 170.1(10.63), 159.1(44.99),
158.1(19.01), 143.1(13.66), 142.1(16.06), 137.1(33.56),
136.1(100), 130.1(47.28), 129.1(15.17), 128.1(16.43),
124.1(14.68), 122.1(11.15), 108.1(16.27), 103.1(10.87),
93.1(12.20), 79.1(24.17), 68.1(25.52). HRMS: calculated
for C H N O: 294.17322; found 294.17326.
2
3
precipitated. The solvent was being distilled off from the
extract until 209 mg of the alkaloids B and C
precipitated, which we were not able to separate. The
mother liquor remaining after the precipitation afforded
1
9 22 2
2
1
IR (KBr, cm ): 3500–2400 (broad absorption with
extrema at 2715 and 2589; hydrogen bonded OH group);
3087, 3065, 3035 (aromatic nC–H); 2930, 2904, 2886, 2856
(aliphatic nC–H); 1590, 1568, 1507 (quinoline nCyC); 1446,
8
Removal of the solvent from the remainder gave
26 mg of the crystalline alkaloids 18 and 6 (C and D).
4
51 mg of C and D.
1
339 (aliphatic d
1
); 1093.1079 ðnC–O?).
C–H
3
0
2.5.1. [4(S)-1(E)-Propenyl-2(S)-piperidinyl]-4-
quinoline-(aR)-methanol 14. Nicinquidine
H NMR (CDCl /TMS). d 8.82 (d, 1H, J ¼ 4:4; H2 );
3
H
3
0
3
0
7.59 (d, 1H, J ¼ 4:6; H3 ); 7.95 (dd?, 1H, J ¼ 8:4; ?, H5 );
3
3
4
0
Column chromatography of the above 826 mg fraction
neutral alumina-Aldrich 82 g; benzene (105 ml); 5% (v/v)
479 ml); 10% (v/v) (333 ml) and 20% (v/v) (187 ml) of
7.33 (ddd, 1H, J ¼ 8:3; J ¼ 7:0; J ¼ 1:1; H6 ); 7.63
3
3
4
0
2
[
(
(ddd, 1H, J ¼ 8:4; J ¼ 7:0; J ¼ 1:2; H7 ); 8.08 (dd, 1H,
3
4
0
3
J ¼ 8:5; J ¼ 1:1; H8 ); 1.97 (ddd, 1H, J ¼ 12:3; J ¼
3
9
9.8% ethanol in benzene; ethanol (176 ml) and methanol
8:4; J ¼ 1:6; H7); ,1.38 (m, 1H, H7); 3.59 (m, 1H, H6);
(
1600 ml)] gave: 20 mg (18, alkaloid C), 85 mg
contaminated 18), 12 mg (C þ D), 404 mg (alkaloid D)
2.67 (m, 1H, H6); 1.79 (m,1H, H5); 1.55 (m, 1H, H5); 2.33
(bs, 1H, SJ , 10; H4); 3.45 (dm, 1H, J ¼ 16:8; H2); 3.32
2
(
and 223 mg (contaminated D).
2
3
5
(dm, 1H, J ¼ 17:0; H2); 5.14 (qt, 1H, J ¼ 6:8; J ¼ 2:4;
3
5
A 109 mg of the alkaloid D from the 404 mg fraction was
dissolved in hot ethanol (1.5 ml) and treated by 102 mg of
oxalic acid [(COOH) ·5H O] in 2.2 ml of ethanol yielding
H10); 1.40 (dt, 3H, J ¼ 6:8; J ¼ 2:4; H11).
0
3
C
1
3
0
0
C NMR (CDCl /TMS). d 149.99 (C2 ); 118.10 (C3 );
0
0
0
149.00 (C4 ); 122.91 (C5 ); 126.50 (C6 ); 128.88 (C7 ):
2
2

Table 2
NMR data for the alkaloids 12 and 14 (C
6
D
6 3
/TMS) and the salt 12.2HCl (CD OD/TMS)
Carbon atom
No.
DEPT 12
12·2HCl
14
Rabe IUPAC
dC
dH
Splitting pattern J (Hz)
dC
dH
Splitting pattern J (Hz)
dC
dH
Splitting pattern J (Hz)
a
9
8
7
a
2
3
CH
CH
CH
72.34
5.22
3.15
1.63
d
4.2
10.9; 3.9; 2.8
69.12 6.13
55.77 3.83
26.85 2.04
1.09
d; (d?)
dt
2.7
72.27
5.15
3.25
1.61
1.24
2.32
1.47
1.31
2.66
2.53
5.26
d(d?)
ddd
ddd
dtd
bs
4.4
55.17
30.37
ddd
ddd
m
bs
m
dqd
m
m
m
m
m
m
t
12.4; 3.0; 3.0
14.3; 12.4; 4.2
55.35
30.39
11.3; 4.2; 3.0
13.2; 11.3; 4.9
13.2; 3.0; 3.0; 1.8
SJ , 22
2
13.2; 11.1; 4.9
ddd
m
b
b
b
b
b
b
1
.09
4
5
4
5
CH
CH
31.03
29.84
1.56
1.40
SJ , 20
30.42 1.94
26.22 1.97
1.72
m
33.94
31.28
2
2
2
2
3
m
tt
12.4; 12.4; 4.6; 4.6
1
.17
2.55
.55
13.2; 3.0; 3.0; 3.0; 1.9
dm
m
13.2; ?
m
6
3
1
6
CH
CH
CH
41.37
33.58
20.80
41.63 3.33
3.33
41.86
133.74
124.98
td
12.4; 12.4; 3.9
2
m
ddd
ddq
12.1; 3.8; 3.6
0
0
0
0
b
b
b
b
c
c
1
2
0.88
.10
0.92
.06
33.33 1.29
1.04
m
15.5; 6.2; 1.5; 1.5; 1.5
b
b
1
m
0
0
21.41 1.06
0.89
m
5.04
dqd
15.4; 6.3; 6.3; 6.3; 1.6
1
m
0
0
0
0
0
1
2
3
4
9
5
6
7
8
1
1
3
2
3
4
CH
CH
CH
14.23
150.60
119.41
149.22
126.37
123.45
126.32
128.95
131.32
147.43
0.63
8.87
7.62
7.0
4.6
4.3
14.19 0.69
145.75 9.25
121.47 8.35
160.19
t
7.0
5.8
5.5
18.11
150.64
119.35
149.23
126.32
123.37
126.25
128.88
131.37
147.00
1.36
8.89
7.60
dt
d
6.2; 1.4; 1.4
4.7
0
d
d
0
0
0
0
0
0
0
d
d
dd
4.7; ,0.8
d
d
4 a
127.16
0
5
CH
CH
CH
CH
7.90
7.17
7.33
8.38
dd
8.5; 1.0
126.00 8.70
132.01 8.10
136.25 8.24
122.86 8.33
139.14
d(d?)
ddd
ddd
dd
8.5; ?
7.82
7.16
7.33
8.38
dd
8.5; ,0.9
8.3; 6.9; 1.4
8.3; 6.9; 1.4
8.5; 0.8
0
0
0
6
ddd
ddd
dd
8.4; 6.9; 1.4
8.5; 6.9; 1.5
8.5; 1.0
8.5; 7.0; 1.4
8.5; 7.0; 1.3
8.5; ?
ddd
ddd
dd
7
e
8
0
0
d
d
0
8 a
a
b
c
d
e
For IUPAC numbering see formula 4, Scheme 1.
13
1
1
1
dH have been taken from C– H- and H– H-cosy spectra.
DEPT: CH.
dc may be interchangeable.
Apart from the dH listed, the alkaloid 14 shows dH ¼ 1:54 s (NH) and dH , 0:7– 1.8 (OH) exchangeable with D
2
O.

172
D. Desperak et al. / Journal of Molecular Structure 705 (2004) 167–176
0
0
0
1
30.20 (C8 ), 125.52 (C9 ); 148.07 (C10 ); 71.78 (C9); 61.19
C8); 28.03 (C7); 44.01 (C6); 27.84 (C5); 33.41 (C4);
mixture was dissolved in 5% HCl (18 ml) and again
hydrogenated as above with fresh Adams catalyst
(11.7 mg) for 14 h. The alkaloid 16 was isolated from
the reaction mixture in a manner described above. Oil,
(
1
40.57 (C3); 56.71 (C2); 114.61 (C10); 12.41 (C11).
2.7. [4(S)-Propyl-2(S)-piperidinyl]-4-quinoline-(aR)-
methanol 12. Dihydronicinquidine. Method B
113 mg., ½aŠ ¼ 238:38 (c ¼ 0:625; ethanol).
d
þ
MS m=z : 287.2 (M –H, 0.33); 169.1(11.45);
64.1(13.12); 163.1(100); 162.(10.07); 126.1(62.29);
1
82.1(5.91);56.6(26.00).
Nicinquidine 14 (300 mg) was dissolved in 5% hydro-
chloric acid (65 ml) and hydrogenated by stirring with
1
3
0
H NMR (C D /TMS): d 8.50 (d, 1H, J ¼ 4:8; H2 );
6
6
H
3
0
0
Adams catalyst (PtO , 5 mg) under hydrogen (slightly
2
7.45 (d, 1H, J ¼ 4:8; H3 ); 2.56 (m, 2H, H5 ); 1.54 (m, 2H,
0
0
0
above atmospheric pressure) at room temperature for 8.5 h.
The catalyst was then removed by filtration and the acidic
filtrate was made alkaline (conc. KOH) and exhaustively
extracted with diethyl ether. The combined extracts were
dried over K CO . Removal of the solvent gave the mixture
H6 ); 1.56 (m, 2H, H7 ); 3.01 (m, 2H, H8 ); 4.73 (d, 1H,
J ¼ 4:9; Ha); 2.93 (m, 1H, H2); 1.68 (m, 1H, H3); 1.36 (m,
3
1H, H3); 1.69 (m, 1H, H4); 1.22 (m,1H, H5); 1.51 (m, 1H,
00
0
0
H5); 2.59 (m, 2H, H6); 1.13 (m, 1H, H1 ); 1.26 (m, 1H, H1 );
00
0
0
3
,1.10 (m, 2H, H2 ); 0.78 (t, 3H, J ¼ 7:0; H3 ) Most of the
2
3
1
d values have been taken from H– H- and H– C-cosy
1
1
13
of 12 and unreacted 14 (260 mg). The mixture was dissolved
in 5% hydrochloric acid (65 ml) and the hydrogenation was
repeated with fresh Adams catalyst (5 mg). The alkaloid 12
H
spectra.
3
1
0
0
C NMR (C D /TMS). d 147.03 (C2 ); 119.71 (C3 );
6
6
C
0 0 0 0
(
229 mg) was isolated using the above described procedure.
157.45 (C4 ); 129.23 (C4 a); 25.76 (C5 ); 22.99 (C6 ); 23.11
0
0
0
Oil, ½aŠ ¼ 254:78 (c ¼ 0:600; ethanol).
(C7 ); 33.56 (C8 ); 149.51 (C8 a); 71.60 (Ca); 54.58 (C2);
30.88 (C3); 31.28 (C4); 30.11 (C5); 41.56 (C6); 33.98
d
þ
MS m=z; 266.3 (M –H O, 4.05); 163.1(12.12);
2
0
0
00
00
1
1
7
1
60.1(14.15); 159.1(100); 158.1(30.03); 130.1(75.10);
29.0(16.20); 126.2(79.85); 103.1(9.94); 82.0(25.21);
(C1 ); 21.00 (C2 ); 14.43 (C3 ).
þ
5.0(10.10); 55.7(91.11). MS FAB m=z 285.4 (M þ H ,
00).
3. Results and discussion
2
1
IR (KBr, cm ): 3600–2400 (broad absorption with
extremum at 3245; hydrogen bonded OH and NH groups);
087, 3038 (aromatic nC–H); 2957, 2926, 2870, 2854
aliphatic nC–H); 1590, 1571, 1509 (quinoline nCyC);
Quinine and cinchonine (1a,b, Scheme 1) during reaction
with hydrobromic acid afford product of addition of HBr to
their vinyl groups (1 ! 2, Scheme 1). The 10-bromo-10,11-
dihydroderivatives 2a,b, exposed to equimolar sodium
bicarbonate in refluxing 80% (v/v) aqueous ethanol,
undergo a new type of rearrangement 2 ! 3 (Scheme 1)
[7,8].
3
(
1
464, 1451, 1367 (aliphatic dC–H); 1100 ðnC–OÞ:
NMR: see Table 2.
2
.7.1. Dihydronicinquidine dihydrochloride 12·2HCl
Forty six mg of 12 dissolved in 99.7% ethanol (1 ml) was
The 8-oxa-1-azabicyclo[4.3.0]nonane derivatives 3 are at
the same time, intermediate products of the reaction (known
since the era of Skraup [11]) during which 10-halo-cinchona
derivatives 2 formally lose their C2 carbon atom extricating
as formaldehyde (2 ! 3 ! 4, Scheme 1) [7,8].
acidified with three drops of concentrated (,36%)
hydrochloric acid yielding 30 mg of the salt. Removal of
the solvent from the mother liquor and recrystallization of
the remainder from methanol gave additional 14 mg of
1
2·2HCl. 160–192 8C gradual darkening, mp: 207–210 8C
Such course of transformation has so far been unstudied
in the case of cinchonidine 1c. This alkaloid treated by 62%
hydrobromic acid provides inseparable C-10 diastereomeric
10-bromo-10,11-dihydrocinchonidines 2c. Therefore only
the mixture of these diastereomers could be used as a
substrate.
(
calculated for C H N O·2HCl (357.325): C, 60.60; H,
decomp.), ½aŠ ¼ 253:38 (c ¼ 0:735; methanol). Analysis
d
1
8 24 2
7
.33: N, 7.83; found: C, 60.23; H, 7.23; N, 7.65%.
NMR: see Table 2.
0
0
0
0
2.8. [4(S)-Propyl-2(S)-piperidynyl]-4-(5 ,6 ,7 , 8 -
tetrahydroquinoline)-(aR)-methanol 16
Crude product, obtained by the action of equimolar
NaHCO on 2c in refluxing 80% (v/v) aqueous ethanol,
3
showed four TLC spots A–D marked in accordance with
increasing polarity. The isolated less polar component A
consisted of two inseparable alkaloids appearing at a ratio
Nicinquidine 14 (103 mg) was dissolved in 5% hydro-
chloric acid (21.5 ml) and hydrogenated by stirring with
1
Adams catalyst (PtO , 11 mg) under hydrogen (slightly
2
76%: 24% , 3:1 ( H NMR integration). Fortunately their
non-aromatic signals on the H and C NMR spectra
1
13
above atmospheric pressure) at room temperature for 12.5 h.
The catalyst was filtered off and the filtrate was made
alkaline (conc. KOH) followed by exhaustive extraction
with diethyl ether. The combined extracts were dried over
K CO and the oily product obtained after removal of the
overlapped only partially. Moreover, their d ; d and J
HH
H
C
values (Table 1) were very close to analogical values for the
E- and Z-diastereomers of 3a (Scheme 1) [7], whereas
splitting patterns of most of the proton resonances were
identical.
2
3
1
solvent showed ( H NMR) the presence of 12 and 16. This

D. Desperak et al. / Journal of Molecular Structure 705 (2004) 167–176
173
Scheme 1. Transformation of cinchona alkaloids 1 into products 4 deficient of carbon atom C2. Numbering in parentheses of formulae 3 and 4 denotes Rabe’s
convention.
1
These results together with analysis of the H- H- and
1
around the substrate atoms C4, C8 and C9 is retained about
the corresponding OABN atoms C4, C6 and C7 [7,8].
Instead, the configuration around N1 atom unnecessarily
remains unchanged. Consequently, formation of cis- or
trans fusion between the OABN five- and six-membered
rings should be considered.
1
3
1
C– H-cosy spectra enabled detection of piperidine ring
for both the alkaloids A. This ring, in the case of dominating
76%) alkaloid is substituted at carbon atom C4 by
E-propenyl group. The E configuration results from
(
3
coupling constant
the chemical shift of the C3 methyl group amounting to
J
00 00 ¼ 15:4 Hz as well as from
H1 H2
00
The trans junction 5 (Scheme 2) may be excluded since
dC values observed for E- and Z-isomers of the discussed
alkaloids (see Table 1) display great similarity with
chemical shifts of carbon atoms C2, C3, C4, C5, C6 and
C7 of the compounds 3a (Scheme 1) featuring cis-junction
[7]. The shifts amount to, respectively, 44.64, 29.02, 33.51,
30.73, 60.28, 77.16 for the E-derivative and 45.65, 29.83,
28.77, 30.52, 60.68, and 76.66 for the Z-isomer [7]. On the
other hand the trans-fused alkaloids demonstrate different dC
values, in particular for the carbons C5. These resonances
appear at d ¼ 32:07 for 3b [8] and at d ¼ 32:40 for
d ¼ 17:99 [12]. The C4 propenyl group of the minor (24%)
C
alkaloid has Z configuration as indicated by d values for C4
C
0
0
and C3 (28.62 and 12.12, respectively; see Table 1)
caused by g-shielding effect analogous to that of model
cis-hexene-2 [12]. The effect does not operate within
trans-hexene-2, i.e. in the E configuration.
1
3
The remaining C NMR data as well as analogy with the
alkaloid 3b (Scheme 1) [8] indicate that positions 2 of
the piperidine rings are substituted by quinol-4-yl-oxy-
methyl groups.
C
C
The 2,4-substituents and the piperidine rings do not
comprise methylene groups featuring d ¼ 86:82 and
9,9-dimethyl derivative of 3a [7]. Moreover, similarly to
structure 3b [8], the trans-junction would have demanded
splitting of one of the C9 proton signals into ‘doublet of
doublets’ due to long distance coupling. Meanwhile the C9
protons resonate as ‘doublets’ (see Table 1).
C
2
geminal coupling constant
J
¼ 2:7 Hz for the
HH
2
dominating alkaloid and d ¼ 87:06 with J ¼ 3:8 Hz
C
HH
for the minor (24%) one. The methylenes also showed no
vicinal proton–proton couplings. These spectral properties
indicate location of each of the CH groups between oxygen
It is also worth mentioning here that conversion of the
cis-compound 3a into its trans-fused variety demanded
action of the packing forces of the crystal lattice [7].
The above discussion and, especially, the close similarity
of the dC values to the chemical shifts of cis-fused 3a
(Scheme 1) [7] allow us to ascribe the cis-junction to the
alkaloids discussed. This fusion, however, may occur in two
2
and nitrogen atoms in oxazolidine ring making a fragment
of 8-oxa-1-azabicyclo[4.3.0]nonane (OABN) system, an
analogue of the compounds 3a,b [7,8].
Because closing of the oxazolidine ring engages the
hydroxylic oxygen and C2 carbon atoms, configuration

174
D. Desperak et al. / Journal of Molecular Structure 705 (2004) 167–176
Scheme 2. Conversions of 10-bromo-10,11-dihydrocinchonidine 2c. Reagents and conditions: (i) NaHCO
4–4.5 atm), Adams PtO , rt, 4 h; (iii) 3–4N HCl, dimedon, hot water bath, 90 min, only reaction of 6 shown; (iv) H
PtO , 26 h, rt.
, 5% HCl, 8.5 þ 8.5 h, rt; (v) conditions as in (iv) with more PtO
3
, 80% aqueous ethanol, 18 h reflux; (ii) H
2
(
2
2
(slightly above atm pressure), Adams
2
2
pairs of conformers being the equilibrium mixtures: 6 X 7
and 8 X 9 (Scheme 2).
The alkaloid featuring E-propenyl side chain
These results indicate predominance of the conformer 6 in
the 6 X 7 equilibrium (Scheme 2).
The minor (24%) alkaloid with Z-configuration of the
3
3
has coupling constant JH6H5 ¼ 9:3 Hz characteristic of
side chain displays coupling constant JH6H5 ¼ 7:8 Hz
1
,2-diaxial orientation of H5 and H6 hydrogens [7]. Its H4
(Table 1). This magnitude cannot arise from 1,2-diaxial
interaction of C5 and C6 protons. Therefore it originates
from averaging of coupling constants between H5 and H6
due to conformational equilibrium 8 X 9 (Scheme 2).
proton signal shows SJ , 22 Hz and this resonance,
excluding 1,2-diaxial interactions with hydrogens on C3
and C5, points to axial position of the E-propenyl group.

D. Desperak et al. / Journal of Molecular Structure 705 (2004) 167–176
175
Occurrence of the latter equilibrium is additionally
supported by the value of the coupling constant of 8.1 Hz
with the five-membered moiety. This manifests itself by
3
change of coupling constants from J
3
¼ 9:3 Hz in 6 to
H5H6
(
Table 1) between protons H2 and H3. In the case of
,2-diaxial interaction between these protons, their
JH2H3 ¼ 11:0 Hz in 12 as well as in the increase of
AX
1
the corresponding dihedral angles from 21478 (for H
C5–C6–HAX) to 21608 (for HAX–C2–C3–HAX).
–
coupling constant should reach 10.7 Hz as shown by
alkaloid 6 (Table 1).
Population of the conformer 9 in the equilibrium mixture
A certain degree of destruction of the oxazolidine ring
also occurs during, both column and TLC, chromatography
on alumina likely caused by the Bronsted acidic centres.
For this reason quantitative chromatographic isolation of the
alkaloids 6 and 8 was impossible. The component D
(see discussion later in the text), formed during acidic
decomposition of 6 and 8, was also an improper factor
determining the share of the 2c ! 6 þ 8 reaction, since we
could not exclude rigorously its formation as a result of
dehydrobromination of 2c. In order to determine as
accurately as possible the content of the rearrangement
products 6 and 8, the crude dehydrobromination product
was treated by hydrochloric acid in the presence of
dimedone to trap the formaldehyde in the reaction vessel.
The amount of the precipitated condensate thus became a
measure of the participation of the 2c ! 6 þ 8 rearrange-
ment. Its share reaches 45–49%.
8
X 9 was estimated using the method of Eliel et al. [13]
and coupling constants of 9.3 Hz, featuring axial protons H5
and H6 of the alkaloid 6, as well as of 2.6 Hz for axial H6
and equatorial H5 of the alkaloid 3b [8]. The calculation
gave 24.6 (^2.3)% of 9 in the 8 X 9 mixture.
The inseparable mixture of the discussed alkaloids A
6 X 7 and 8 X 9, Scheme 2) subjected to catalytic
(
hydrogenation afforded the propyl derivative. In spite of
certain degree of unavoidable over-reduction, this
hydrogenated alkaloid confirms structure of the E- and
Z-substrates. In addition, the value of coupling constant
3
JH6H5 ¼ 7:2 Hz (Table 1) allows us to accept that the
hydrogenation product is an equilibrium mixture of
conformers 10 X 11 (Scheme 2). Interestingly, the mixture
00
exhibits NOE between C1 proton (at d ¼ 0:95) and
H
protons at C6 ðd ¼ 3:45Þ and C2 ðd ¼ 2:63Þ: This effect
Formation of the condensate during decomposition of the
compounds 6 and 8 also confirms their role as the
intermediates [7,8] preceding the loss of the carbon C2 by
the alkaloid 2c.
H
H
would indicate the dominance of the conformer 10 over the
one of 11. Indeed, this result agrees with 31.3% population
of 11 estimated by means of the Eliel method [13] and the
above mentioned coupling constants 9.3 and 2.6 Hz.
According to expectance [7,8], the oxazolidine ring of
the propylo derivative decomposes in acidic medium losing
its C9 methylene group. This fragment, corresponding to C2
methylene of the parent cinchonidine, is eliminated as
formaldehyde which was trapped as a condensation product
with dimedone (10 X 11 ! 12, Scheme 2).
The component D resulting from the decomposition was
separated from the remaining alkaloids B and C and then
transformed into acid oxalate to provide the purified
alkaloid. Its NMR data (Table 2) indicated the presence of
piperidine ring substituted at C4 by E-propenyl group
3
( J 00 00 ¼ 15.4 Hz, methyl group of d ¼ 18:11 [12]) and
H1 H2
C
at C2 by quinol-4-yl-oxy-methyl group.
The obtained alkaloid (dihydronicinquidine) features
The discussion (vide supra) concerning the configuration
of atoms C4, C6 and C7 in the OABN derivatives 6, 8 and
12 also holds for corresponding C4, C2 and Ca atoms of the
decomposition product considered. Hence, occurrence of
this compound as an equilibrium mixture 14 X 15
3
1
,2-diaxial coupling constant JH3H2 ¼ 11:0 Hz as well as
00
an Overhauser effect between protons at C1 ðd ¼ 0:88Þ
H
and at C2 ðd ¼ 3:15Þ: These data and the dihedral angle
H
H–C2–C3–H of 21608 calculated according to Altona
1
[14] point to the dominance of the conformer 12 in the
equilibrium mixture 12 X 13.
(Scheme 2) should be taken into account. The H NMR
signal of the C4 proton (Table 1) appearing as a ‘broadened
singlet’ with SJ , 22 Hz (which eliminates 1,2-diaxial
coupling with C3 and C5 protons) and coupling
Formation of the alkaloid 12 from 10 is not accompanied
by its Ca epimer. Similar process also takes place during
action of an acid onto alkaloids 3a,b (Scheme 1) [7,8] and is
due to breaking of the C9–O bond whereas the C7–O bond
remains intact [7,8,15]. As a consequence, Ca atoms of
nicinquine 4b [15] and niquine 4a [7] (Scheme 1) preserve,
respectively, the S and R arrangements around the C9 atoms
of the parent alkaloids [16] corresponding to C7
configuration of the OABN moieties. Since the presence
or absence of the quinoline 6-methoxy group exerts no
influence on the retention of the Ca configuration, such
retention should take place in the alkaloid 12 derived from
cinchonidine a demethoxy analogue of quinine.
3
constant JH6axH5ax ¼ 11:3 Hz (with the corresponding
H6AX–C6–C5–H5AX dihedral of 21648 [14]) clearly
point to predominance of the conformer 14. In addition,
axial protons on C2 ðd ¼ 3:25Þ and C6 ðd ¼ 2:66Þ display
H
H
0
0
an NOE with C1 proton ðd ¼ 5:26Þ:
H
By analogy with niquine 4a and nicinquine 4b
(Scheme 1), the alkaloid 14 was named nicinquidine.
Nicinquidine subjected to catalytic hydrogenation
provided dihydronicinquidine 14 ! 12 (Scheme 2) identi-
cal with the product of the acidic ‘fragmentation’ 10 ! 12
(Scheme 2).The alkaloid 12 was also characterized by its
dihydrochloride (12·2HCl). Localization of nitrogen atom
in the non-aromatic moiety of the salt was confirmed by
The discussed acidic fission of the oxazolidine fragment,
apart from formal lost of the C9 carbon, relieves
tension within the piperidine ring caused by its fusion
1
3
protonation effects. They caused up-field shift of the
C

176
D. Desperak et al. / Journal of Molecular Structure 705 (2004) 167–176
NMR signals of the carbons b in relation to the piperidinic
nitrogen [17], i.e. to Ca, C3 and C5 as compared with the
free alkaloid 12 (Table 2).
Carrying out the reaction 14 ! 12 required
experimental finding of the hydrogenation conditions
which on the one hand would assure reduction of the
propenyl group but on the other hand would prevent from
10(R) diastereomer of 2c would be responsible, similarly as
in the case of 10(R)-bromo-10,11-dihydroquinine [7].
Unfortunately this analogy could not be verified
experimentally since compounds 2c were inseparable.
In conclusion, despite the above inconvenience, the
scope of the new rearrangement extends to cinchonidine,
another main Cinchona alkaloid.
(
rather difficult to avoid) over-reducing in the quinoline
ring. During the search we found, that apart from
reduction of the side chain, hydrogenation of benzene
fragment of the quinoline ring took place (14 ! 16 X 17,
Scheme 2; the NMR data see Section 2.8). Because of
Acknowledgements
We thank Professor Władysław Boczo n´ for supporting
this study from his funds.
1
severe overlapping of the non-aromatic resonances, the H
NMR spectra of the obtained ‘hexahydronicinquidine’
precluded drawing of accurate stereostructural
1
3
conclusions. However, the C NMR data show that
piperidine fragment of this compound preserves similarity
to the piperidine moiety of 12. Therefore, one may
suppose that the over-reduced derivative exists as an
equilibrium mixture of conformers 16 X 17 (Scheme 2).
Besides the above described rearrangement 2c ! 6 þ 8,
References
[
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3
3
,10
elimination of HBr. As a result the D -derivative 18
Scheme 2) arises corresponding to the component C. (We
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(
6
[
5] W.M. Braje, J. Frackenpohl, O. Schrake, R. Wartchow, W. Beil,
H.M.R. Hoffmann, Helv. Chim. Acta 83 (2000) 777.
component B). The alkaloid 18 features mp 236–238 8C
(
decomp.) and ½aŠ ¼ 2126:78. This compound exhibits
d
[6] T. Zheng, J. Flippen-Anderson, P. Yu, T. Wang, R. Mirghani, J.M.
Cook, J. Org. Chem. 66 (2001) 1509.
d ¼ 33:41 for the methine carbon C4. This value, in
C
[
[
[
7] J. Thiel, A. Katrusiak, Tetrahedron: Asymmetry 13 (2002) 47.
8] J. Thiel, P. Fiedorow, J. Mol. Struct. 440 (1998) 203.
comparison with model 3-ethylidenequinuclidine [18],
indicates Z-configuration of the side chain (In the case of
the E-configuration the C4 resonance should have appeared
9] H. Thron, W. Dirscherl, Justus Liebigs Ann. Chem. 515 (1935) 252.
[
10] W. Solomon, J. Chem. Soc. (1941) 77.
at d ¼ 26 ^ 1:). The Z-arrangement is additionally sup-
C
[11] H. Zd, Skraup, Monatsh. Chem. 14 (1893) 428.
[12] P.A. Couperus, A.D.H. Clague, P.C.M. van Dongen, Org. Magn.
Reson. 8 (1976) 426.
ported by NOE between protons at C4 (d ¼ 2:33; broad
H
singlet, SJ , 10 Hz) and C10 (d ¼ 5:14; qt, J ¼ 6:8 and
H
[
13] E.L. Eliel, S.H. Wilen with a Contribution by L.N Mander,
Stereochemistry of Organic Compounds, Wiley, New York, 1994,
pp. 641–642.
2.4 Hz). Two isomeric 3,10-didehydro-10,11-dihydrocinch-
onidines with undetermined E- and Z-configurations were
described earlier [19]. One of them showed mp
[
14] C.A.G. Haasnoot, C. de Leuw, C. Altona, Tetrahedron 36 (1980) 2783.
2
2
1
54.7–256.7 8C and ½aŠ ¼ 21348 the other had mp
[15] T. Borowiak, G. Dutkiewicz, J. Thiel, Z. Naturforsch, 55b
(2000) 1020.
d
40–241 8C (decomp.) and ½aŠ ¼ 2126:68. The alkaloid
d
[
[
16] G.G. Lyle, L.K. Keefer, Tetrahedron 23 (1967) 3253.
8 is most likely identical with the other compound.
Formation of 18 points to considerable share of
17] J.E. Sarneski, H.L. Surprenant, F.K. Mollen, C.N. Reiley, Anal. Chem.
4
7 (1975) 2116.
stereoselective elimination accompanying stereoselective
rearrangement 2c ! 6 þ 8 (3:1). One may suppose, that for
the dominance of the alkaloid 6, the exclusive conversion of
[
[
18] G. van Binst, D. Tourve, Org. Magn. Reson. 4 (1972) 625.
19] T.A. Henry, The Plant Alkaloids, fourth ed., vol. 4, Churchil, London,
1949, p. 452.