Novel synthesis of indolizidines and quinolizidines

Article abstract of DOI:10.1016/S0040-4020(03)00375-2

A very short synthesis of indolizidines, quinolizidines and some higher homologues was developed by alkylation of 2-methyl-1-pyrroline or 6-methyl-2,3,4,5-tetrahydropyridine with 1,3- or 1,4-dihaloalkanes, followed by reduction of the intermediate iminium salts, resulting in the desired 1-azabicyclo[m.n.0]alkanes in good yields.

Full text of DOI:10.1016/S0040-4020(03)00375-2

Tetrahedron 59 (2003) 3099–3108
Novel synthesis of indolizidines and quinolizidines
†
Kourosch Abbaspour Tehrani, Matthias D’hooghe and Norbert De Kimpe
*
Department of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, Ghent University, Coupure Links 653,
B-9000 Ghent, Belgium
Received 16 September 2002; revised 5 March 2003; accepted 6 March 2003
Abstract—A very short synthesis of indolizidines, quinolizidines and some higher homologues was developed by alkylation of 2-methyl-1-
pyrroline or 6-methyl-2,3,4,5-tetrahydropyridine with 1,3- or 1,4-dihaloalkanes, followed by reduction of the intermediate iminium salts,
resulting in the desired 1-azabicyclo[m.n.0]alkanes in good yields. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
annulation of cyclic enamines, stabilized by electron-
withdrawing groups, with acryloyl chloride was developed
as a synthesis of 1-azabicyclo[4.3.1]nonanes.27
In the past three decades, a whole range of biological active
alkaloids has been isolated from amphibian skin. Especially
frogs from the Dendrobatidae,1 Mantellinae,2 Myobatra-
chidae and Bufonidae3 families contain a wide variety of
lipophilic skin alkaloids. These compounds consist mainly
of bicyclic and also tricyclic structures bearing a single
nitrogen atom. Among others, pyrrolizidines, di- and
trisubstituted indolizidines and disubstituted quinolizidines
have been characterized. Many of these compounds, e.g.
pumiliotoxins, have caught the attention of the medical
world due to their potential physiological activities.4–7
Furthermore, interesting alkaloids were isolated from
plants, e.g. ajmaline found in the roots of Rauwolfia
serpentina,8 and also from micro-organisms, e.g. the
broad-spectrum antibiotic lemonomycin produced by
Streptomyces candidus.9
In the present report, a very short, reliable and efficient
synthesis of alkyl substituted indolizidines, quinolizidines
and also larger bicyclic ring systems is presented. The
general strategy consists of deprotonation at the a-position
of a cyclic imine, such as 2-methyl-1-pyrroline and
6-methyl-2,3,4,5-tetrahydropyridine, followed by reaction
with a v,v0-dihaloalkane. The resulting bicyclic iminium
salt is then further transformed into the desired
1-azabicyclo[m.n.0]alkane by reduction (Scheme 1).
The synthetic strategies towards 1-azabicyclo[m.n.0]-
alkanes are in general either long and inefficient, or rather
expensive due to the use of some less common reagents.
Many synthetic designs presented in the past made use of a
radical10–15 or a reductive cyclization method.16–19 Also
cycloaddition20–22 and metathesis reactions23,24 have been
explored. One remarkable example of a bicyclic enamine
synthesis is known in the literature, in which deprotonation
of 6-methyl-2,3,4,5-tetrahydropyridine and alkylation with
1-chloro-3-iodopropane resulted in the corresponding
bicyclic enamine.25,26 However, in this case, the inter-
mediate iminium salt was not trapped but in situ converted
into the enamine by treatment with base. Finally, aza-
Scheme 1.
The numbering and nomenclature of indolizidines and
quinolizidines was performed according to the literature
(Fig. 1).28 In substituted indolizidines and quinolizidines the
descriptors cis and trans are related to the relative position
of the hydrogen atom on the carbon atom 8a and 9a (for
indolizidines and quinolizidines, respectively) with respect
to the hydrogen atom on the substituted carbon atom.
Keywords: iminium salts; reduction; indolizidines.
*
Corresponding author. Tel.: þ32-9-264-5951; fax: þ32-9-264-6243;
e-mail: norbert.dekimpe@rug.ac.be
Department of Organic Chemistry, Vrije Universiteit Brussel, Pleinlaan
2, B-1050 Brussels, Belgium.
†
Figure 1.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00375-2

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K. Abbaspour Tehrani et al. / Tetrahedron 59 (2003) 3099–3108
Scheme 2.
2. Results and discussion
cis- and trans-5-methylindolizidine 11 could be obtained by
means of preparative gas chromatography (Scheme 2).
Kinetic deprotonation of 2-methyl-1-pyrroline 4 with LDA
at 2788C and consecutive reaction with 1-bromo-3-
chloropropane resulted in a bicyclic iminium salt 6, which
was characterized spectroscopically (1H NMR, 13C NMR,
IR). This stable salt was formed after work-up, upon
prolonged evaporation of the solvent. Apparently the
intermediate 2-(4-chlorobutyl)-1-pyrroline 5, which was
not isolated, is transformed quickly into the indolizidinium
salt. After reduction of this salt with lithium aluminum
The relative stereochemistry of indolizidine 11 was
unequivocally determined using nOe experiments (Fig. 2).
In the infrared spectra the typical ‘Bohlmann bands’
appeared at 2770 and 2795 cm21 for the cis- and trans-
isomer, respectively, indicating that the bicyclic structures
were trans-fused.50–52 The appearance of a triplet£doublet
(at 3.24 and 2.81 ppm for cis- (3Ha) and trans-11 (3He),
respectively) and a quadruplet (at 1.97 and 2.54 ppm for cis-
(3He) and trans-11 (3Ha), respectively) in 1H NMR (CDCl3)
also indicates a trans-fused system, in accordance with the
literature.53 The reported data of cis- and trans-5-methyl-
indolizidine 11, prepared from trans-5-cyanoindolizidine,
correspond well with the data obtained here.54
¨
hydride in diethyl ether, d-coniceıne 7 was isolated
(Scheme 2). This bicyclic compound is a frequent target
in indolizidine chemistry.29–49
The outlined method is also applicable for the preparation of
methyl substituted indolizidines. For this purpose, the
alkylation was performed with 1-bromo-3-chloro-2-methyl-
propane and 1,3-dibromobutane. In both cases an inter-
mediate iminium salt was isolated, which was reduced with
LiAlH4. In this way two diastereomeric isomers were
formed, in a ratio of 10:90 for trans- and cis-6-methyl-
indolizidine 9 and 25:75 for trans- and cis-5-methyl-
indolizidine 11, as determined by gas chromatography.
These isomers could not be separated by flash chromato-
grapy (silica gel). Fortunately, analytical pure samples of
The synthesis of 8-substituted indolizidines was realized
starting from 2-methyl-1-pyrroline 4 by two consecutive
alkylations. The first time allylbromide was used as an
electrophile, resulting in 2-(3-butenyl)-1-pyrroline 12. After
a second deprotonation with LDA, followed by reaction
with 1-bromo-3-chloropropane, a salt was formed during
work-up. Spectral analysis confirmed the structure of this
8-allylindolizidinium chloride 13. Hydride reduction gave
rise to two diastereomers trans-14 and cis-14, in a ratio of
35:65, which could be separated by preparative gas
chromatography (Scheme 3).
Besides substituted indolizidines also larger ring systems
become accessible by variation of the alkylating reagent, as
illustrated by using 1-bromo-4-chlorobutane. In this case the
intermediate 2-(5-chloropentyl)-1-pyrroline 15 was
Figure 2.

K. Abbaspour Tehrani et al. / Tetrahedron 59 (2003) 3099–3108
3101
Scheme 3.
Scheme 4.
Scheme 5.

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K. Abbaspour Tehrani et al. / Tetrahedron 59 (2003) 3099–3108
in methanol/THF (1:1), the bicyclic a-aminonitril 6-cyano-
1-azabicyclo[4.4.0]decane 26 was isolated, which can be
useful for further elaboration (Scheme 6).
Methyl-substituted quinolizidines were synthesized using
1-bromo-3-chloro-2-methylpropane and 1,3-dibromo-
butane, after deprotonation of 6-methyl-2,3,4,5-tetrahydro-
pyridine with LDA. In both cases reduction of the
quinolizidinium salts yielded two diastereomers, in a ratio
of 85:15 for trans-23 and cis-23 and 40:60 for trans-25 and
cis-25. By means of preparative gas chromatography,
analytical pure samples of cis-23 and trans-25 were isolated
(Scheme 5).
Scheme 6.
isolated, which showed to be remarkably stable. Attempted
distillation of this 1-substituted pyrroline (1208C/
0.05 mm Hg) resulted in an iminium salt 16, which was
reduced to the desired 1-azabicyclo[5.3.0]decane 17
(Scheme 4). This azabicyclic skeleton is found as a
structural unit in the alkaloids stemoamide and stenine,
isolated from the roots of Stemona tuberosa.55
In the literature, spectrometric data (1H NMR and 13C
NMR) of the methyl-doublet of 23 are reported.28,57 For cis-
and trans-3-methylquinolizidine 23 the spectrometric data
of the methyl-doublet both were in accordance with the
literature. For cis- and trans-4-methylquinolizidine 25,
however, the reported coupling constants28,57 were the
opposite of the experimentally obtained data; the reported
value for the cis-isomer corresponds with the data
obtained here for the trans-isomer and vice versa. Infrared
spectroscopy indicated that all quinolizidines were
Extension of this general method towards the synthesis of
quinolizidines was performed using 6-methyl-2,3,4,5-tetra-
hydropyridine 18. This cyclic imine was prepared from
2-methylpiperidine according to a known procedure.56
Alkylation with 1-bromo-3-chloropropane and reduction
of the obtained quinolizidinium salt 20 with LiAlH4 resulted
in 1-azabicyclo[4.4.0]decane 21 (Scheme 5). When the
quinolizidinium salt 20 was reacted with potassium cyanide
Scheme 7.

K. Abbaspour Tehrani et al. / Tetrahedron 59 (2003) 3099–3108
3103
trans-fused,28 as can be derived from the following
absorbances: 2799 cm21 and 2763 cm21 for cis- and
trans-3-methylquinolizidine 23; 2784 and 2745 cm21 for
cis- and trans-4-methylquinolizidine 25 and 2817 and
2768 cm21 for 6-cyano-1-azabicyclo[4.4.0]decane 26.
dry THF, was added dropwise. The reaction mixture was
then stirred at 2788C for 2 h. Finally a solution of 2.56 g
(0.021 mol) of allylbromide in 20 mL of dry THF was added
slowly, after which the reaction mixture was stirred for 16 h
at room temperature. Work-up was carried out by pouring
the reaction mixture in 75 mL of a 0.5 M sodium hydroxide
solution, followed by extraction with ether (2£75 mL,
1£50 mL). After drying of the organic phase with K2CO3
and filtration of the drying agent, the solvent was removed
in vacuo. Distillation (69–778C/40 mm Hg) yielded 1.77 g
(72%) of compound 12 as a light-yellow liquid. Compounds
6, 8, 10, 13, 20, 22 and 24 were obtained as solids upon in
vacuo evaporation of the ethereal extract, followed by
removal of final traces of solvent under high vacuum
(0.01 mm Hg). Because of the extreme hygroscopicity of
these salts, it was irrelevant to measure the melting points
(broad melting point range). The purity of these salts was
sufficiently high (.95%) to use them as such in the next
step.
Although bicyclic structures with a seven-membered ring
annelated to a six-membered ring frequently occur in
alkaloids, for example in lemonomycin,9 very little
synthetic strategies towards these alkaloids are known. In
one article a rather long synthesis of such a type of iminium
salt is reported starting from a N-functionalised d-lactam, in
a low yield.58 The alkylation of 6-methyl-2,3,4,5-tetra-
hydropyridine 18 with 1-bromo-4-chlorobutane offers an
excellent alternative. The intermediate 6-(5-chloropentyl)-
2,3,4,5-tetrahydropyridine 27 was isolated in 90% yield.
After heating this imine at 1158C for 4 h (neat), an iminium
salt 28 was obtained, which was transformed into 1-aza-
bicyclo[5.4.0]undecane 29 by reduction with LiAlH4.
Treatment of the intermediate 6-substituted tetrahydro-
pyridine 27 with hydride resulted in a mixture of 29%
1-azabicyclo[5.4.0]undecane 29 and 71% 2-(5-chloro-
pentyl)piperidine 30 (Scheme 7). This proves that the
preparation of the bicyclic amine is far more efficient using
the iminium salt method instead of direct reductive
cyclization of a v-chloroimine. Finally, 1-bromo-5-chloro-
pentane was used as an electrophile. The resulting
v-chloroimine 31 was isolated and heated to 1408C for
4 h (neat). Although the product was partially decomposed,
a signal in 13C NMR (210 ppm (CvNþ); DMSO) indicated
the presence of the desired iminium salt 32. Direct reduction
of the alkylated tetrahydropyridine yielded the correspond-
ing piperidine derivative 33 exclusively, without any
cyclization to the bicyclic amine (Scheme 7).
1
3.1.1. 2-(3-Butenyl)-1-pyrroline 12. H NMR (270 MHz,
CDCl3): d 1.86 (2H, quint, J¼7.84 Hz, CH2CH2N); 2.26–
2.52 (6H, m, CH2(CH2)2N and (CH2)2CHvCH2); 3.72–
3.85 (2H, m, CH2N); 4.99 (1H, d£d, J¼10.23, 0.66 Hz,
CHv(HCHcis)); 5.04 (1H, d, J¼17.16 Hz, geminal
coupling not visible, CHv(HtransCH)); 5.79–5.93 (1H, m,
CHvCH2). 13C NMR (68 MHz, CDCl3):
d 22.55
(CH2CH2N); 30.40 and 32.99 ((CH2)2CHvCH2); 37.29
(CH2(CH2)2N); 60.77 (CH2N); 114.95 (CHvCH2); 137.73
(CHvCH2); 177.66 (CvN). IR (NaCl, cm21): 1639
(nCvN); 3077 (nCvHCH). MS (70 eV): m/z (%): 123 (Mþ,
24); 122 (100); 120 (8); 108 (26); 96 (14); 95 (14); 94 (19);
83 (6); 82 (8); 80 (7); 68 (5); 67 (16); 55 (11); 54 (12). Anal.
calcd for C8H13N: C 77.99%; H 10.64%; N 11.37%. Found:
C 77.85%; H 10.86%; N 11.29%.
3.1.2. 2,3,5,6,7,8-Hexahydro-1H-indolizinylium chloride
1
3. Experimental
6. Yield 90%, yellow–orange salt. H NMR (270 MHz,
CDCl3): d 2.00–2.15 (4H, m, CH2(CH2)2CH2Nþ); 2.34
(2H, quintet, J¼7.90 Hz, CH2CH2CH2CvNþ); 2.95 (2H,
broad s, CH2CvNþ); 3.36 (2H, t, J¼7.92 Hz, CH2CvNþ);
3.84 (2H, broad s, CH2Nþ); 4.30 (2 H, t, J¼7.60 Hz,
CH2Nþ). 13C NMR (68 MHz, CDCl3): d 15.74 and 19.37
(CH2(CH2)2CH2Nþ); 17.11 (CH2CH2CH2CvNþ); 26.97
(CH2CvNþ); 38.04 (CH2CvNþ); 47.21 (CH2Nþ); 59.79
(CH2Nþ); 189.24 (CvNþ). IR (NaCl, cm21): 1650
(nCvNþ).
1H NMR spectra were recorded at 270 MHz (JEOL JNM-
EX 270) with CDCl3 as solvent and tetramethylsilane as
internal standard. 13C NMR spectra were recorded at
68 MHz (JEOL JNM-EX 270) with CDCl3 as solvent.
Mass spectra were obtained with a mass spectrometer
(VARIAN MAT 112, 70 eV) using a GC-MS coupling
(RSL 200, 20 m glass capillary column, i.d. 0.53 mm, He
carrier gas). IR spectra were measured with a Perkin–Elmer
1310 spectrophotometer or a Spectrum One FT-IR.
Dichloromethane was dried over calcium hydride. Methanol
was dried by distillation over magnesium, while diethyl
ether and THF were dried by distillation over sodium
benzophenone ketyl. Other solvents were used as received
from the supplier.
3.1.3. 2,3,5,6,7,8-Hexahydro-6-methyl-1H-indoli-
1
zinylium chloride 8. Yield 95%, yellow–orange salt. H
NMR (270 MHz, CDCl3): d 1.72 (3H, d, J¼6.27 Hz, Me);
1.70–1.92 (6H, m, CH2CH2Nþ and (CH2)2CH2CvNþ);
2.28–2.53 (4H, m, 2£CH2CvNþ); 2.68–2.84 (2H, m,
CH2Nþ); 3.06–3.22 (1H, m, MeCH). 13C NMR (68 MHz,
CDCl3): d 15.29; 18.06; 28.27 (CH2CH2Nþ and (CH2)2-
CH2CvNþ); 18.42 (Me); 28.73 (CH2CvNþ); 39.78
(CH2CvNþ); 54.93 (CH2Nþ); 58.58 (MeCH); 191.25
(CvNþ). IR (NaCl, cm21): 1672 (nCvNþ).
3.1. General procedure for the alkylation of 2-methyl-1-
pyrroline 4 and 6-methyl-2,3,4,5-tetrahydropyridine 18
As an example, the synthesis of 2-(3-butenyl)-1-pyrroline
12 is described. To a solution of 2.23 g (0.022 mol)
diisopropylamine in 20 mL of dry THF at 08C was added
slowly via a septum 8.8 mL of n-butyllithium (0.022 mol,
2.5 M in hexane) under nitrogen atmosphere. After 5
minutes this solution was cooled to 2788C and 1.66 g
(0.02 mol) of 2-methyl-1-pyrroline 4, dissolved in 20 mL of
3.1.4. 2,3,5,6,7,8-Hexahydro-5-methyl-1H-indoli-
1
zinylium bromide 10. Yield 96%, yellow–orange salt. H
NMR (270 MHz, CDCl3): d 1.09 (3H, d, J¼6.93 Hz,
MeCH); 1.47–1.67 (1H, m); 1.75–1.92 (4H, m);

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K. Abbaspour Tehrani et al. / Tetrahedron 59 (2003) 3099–3108
2.31–2.41 (2H, m); 2.33–2.52 (2H, m); 3.44–3.53 (2H, m,
CH2Nþ); 3.72–3.84 (2H, m, CH2Nþ). 13C NMR (68 MHz,
CDCl3): d 18.01 (Me); 18.38; 25.00; 26.76; 28.07; 38.72
(4£CH2 and CH); 54.03 and 60.65 (2£CH2Nþ). IR (NaCl,
cm21): 1685 (nCvNþ).
2£CH2CvNþ); 3.79–3.94 (4H, m, 2£CH2Nþ). 13C NMR
(68 MHz, CDCl3): d 16.86 (2£CH2CH2CvNþ); 20.74 (2£
CH2CH2Nþ); 33.06 (2£CH2CvNþ); 54.30 (2£CH2Nþ);
187.02 (CvNþ). IR (NaCl, cm21): 1686 (nCvNþ).
3.1.9. 1,2,3,4,6,7,8,9-Octahydro-3-methylquinoli-
1
zinylium chloride 22. Yield 80%, yellow–orange salt. H
3.1.5. 2,3,5,6,7,8-Hexahydro-8-(2-propenyl)-1H-indoli-
1
zinylium chloride 13. Yield 80%, yellow–orange salt. H
NMR (270 MHz, CDCl3): d 1.06 (3H, d, J¼6.60 Hz, CH3);
1.57–1.74 (2H, m, CHCH2CH2CvNþ); 1.83–2.01 (2H, m,
CH2CH2CvNþ); 2.03–2.13 (2H, m, CH2(CH2)2CvNþ);
2.22–2.48 (1H, m, CH); 2.86–3.02 (4H, m, 2£CH2CvNþ);
3.39–3.53 (1H, m, CH(HCH)Nþ); 3.68–3.88 (3H, m,
CH(HCH)Nþ and CH2CH2Nþ). 13C NMR (68 MHz,
CDCl3): d 16.93 (CH2CH2CvNþ); 18.17 (CH3); 20.75
(CH2(CH2)2CvNþ); 25.05 (CH2CH2CvNþ); 26.81 (CH);
32.96 and 33.67 (2£CH2CvNþ); 54.39 (CH2CH2Nþ);
60.38 (CHCH2Nþ); 186.95 (CvNþ). IR (NaCl, cm21):
1688 (nCvNþ).
NMR (270 MHz, CDCl3):
d
1.63–1.79 (1H, m,
CH(HCH)(CH2)2Nþ); 1.95–2.18 (3H, m, CH(HCH)CH2-
CH2Nþ); 1.21–2.50 (3H, m, CH2CH2CH2Nþ and
CH(HCH)CHvCH2); 2.58–2.71 (1H, m, CH(HCH)CHv
CH2); 3.06–3.21 (1H, m, CHCH2CHvCH2); 3.29–3.48
(2H, m, CH2(CH2)2Nþ); 3.80–3.94 (2H, m, CH(CH2)2-
CH2Nþ); 4.36 (2H, t, J¼7.59 Hz, (CH2)2CH2Nþ); 5.17 (1H,
d£d, J¼9.08, 1.22 Hz, CHv(HCHcis)); 5.19 (1H, d£d,
J¼16.50, 1.22 Hz, CHv(HtransCH)); 5.69–5.86 (1H, m,
CHvCH2). 13C NMR (68 MHz, CDCl3): d 18.20 (CH2-
CH2CH2Nþ); 19.26 (CHCH2CH2CH2Nþ); 22.21 (CHCH2-
(CH2)2Nþ); 35.60 (CH2CHvCH2); 37.75 (CH2CvNþ);
37.90 (CHCvNþ); 48.73 (CH(CH2)2CH2Nþ); 61.26
((CH2)2CH2Nþ); 119.01 (CHvCH2); 133.80 (CHvCH2);
192.16 (CvNþ). IR (NaCl, cm21): 1679 (nCvNþ); 3079
(nvC–H).
3.1.10. 1,2,3,4,6,7,8,9-Octahydro-4-methyl-quinoli-
1
zinylium bromide 24. Yield 80%, yellow–orange salt. H
NMR (270 MHz, CDCl3): d 1.54 (3H, d, J¼6.93 Hz, CH3);
1.76–2.08 (6H, m, CH2(HCH)CH(Me)Nþ and CH2-
(HCH)CH2Nþ); 2.09–2.22 (1H, m, (HCH)CH2Nþ); 2.31–
2.46 (1H, m, (HCH)CH(Me)Nþ); 2.98 (4H, broad s,
2£CH2CvNþ); 3.88 (2H, broad s, CH2Nþ); 4.04 (1H,
broad s, CH). 13C NMR (68 MHz, CDCl3): d 13.78
(CH2CH2CHNþ); 17.09 (CH2(CH2)2Nþ); 18.60 (CH3);
21.11 (CH2CH2Nþ); 27.53 (CH2CH(Me)Nþ); 33.64 and
33.69 (2£CH2CvNþ); 52.69 (CvNþCH2); 59.89 (CH);
187.90 (CvNþ). IR (NaCl, cm21): 1672 (nCvNþ).
3.1.6. 2-(5-Chloropentyl)-1-pyrroline 15. Yield 97%,
colorless liquid. 1H NMR (270 MHz, CDCl3): d 1.42–
1.58 (2H, m, Cl(CH2)2CH2); 1.59–1.70 (2H, m, ClCH2-
CH2); 1.75–1.92 (4H, m, CH2CH2N and Cl(CH2)3CH2);
2.35 (2H, t, J¼7.25 Hz, CH2CvN); 2.47 (2H, t, J¼7.40 Hz,
CH2CvN); 3.54 (2H, t, J¼6.80 Hz, CH2Cl); 3.80 (2H, t£t,
J¼7.26. 1.65 Hz, CH2N). 13C NMR (68 MHz, CDCl3): d
22.53 (Cl(CH2)3CH2); 25.59 (ClCH2CH2); 26.72
(Cl(CH2)2CH2); 32.38 (CH2CH2N); 33.51 (CH2CvN);
37.29 (CH2CvN); 44.87 (CH2Cl); 60.68 (CH2N); 178.18
(CvN). IR (NaCl, cm21): 1640 (nCvN). MS (70 eV): m/z
(%): no Mþ; 138 (Mþ2Cl, 10); 122 (5); 110 (11); 108 (3);
96 (18); 94 (2); 84 (9); 83 (100); 82 (26); 81 (7); 69 (4); 68
(6); 67 (5); 55 (16); 54 (7); 44 (2); 43 (2); 42 (16); 41 (26).
Anal. calcd for C9H16ClN: C 62.24%; H 9.29%; N 8.06%.
Found: C 62.08%; H 9.37%; N 8.16%.
3.1.11. 6-(5-Chloropentyl)-2,3,4,5-tetrahydropyridine
27. Yield 90%, colorless liquid. 1H NMR (270 MHz,
CDCl3):
d
1.41–1.72 (8H, m, ClCH2(CH2)2 and
NCH2(CH2)2); 1.79–1.86 (2H, quint, J¼6.93 Hz, Cl(CH2)3-
CH2); 2.06–2.20 (4H, m, 2£CH2CvN); 3.51–3.60 (4H, m,
CH2Cl and CH2N). 13C NMR (68 MHz, internal standard
CDCl3): d 19.34; 21.67; 25.30 and 26.42 (NCH2(CH2)2 and
ClCH2(CH2)2); 28.93 (CH2CvN); 32.18 (Cl(CH2)3CH2);
40.43 (CH2CvN); 44.71 (CH2Cl); 48.92 (CH2N); 170.87
(CvN). IR (NaCl, cm21): 1662 (nCvN). MS (70 eV): m/z
(%): 187 (Mþ, 1); 152 (17); 138 (2); 124 (8); 110 (15); 97
(100); 96 (26); 82 (7); 70 (11); 55 (10). Anal. calcd for
C10H18ClN: C 63.99%; H 9.67%; N 7.46%. Found: C
64.12%; H 9.79%; N 7.37%.
3.1.7. 1,2,3,5,6,7,8,9-Octahydro-1H-pyrrolo[1,2-a]aze-
pinylium chloride 16. By heating of compound 15 at
1208C (oil bath), the initial liquid solidified after 1 h. The
solid was washed with dry diethyl ether in order to remove
the impurities and the yellow-orange residue was placed
under high vacuum (0.01 mm Hg) in order to remove trace
amounts of solvent. Yield 85%. 1H NMR (270 MHz,
CDCl3): d 1.7–2.00 (6H, m, (CH2)3CH2CvNþ); 2.37
(2H, quintet, J¼7.92 Hz, CH2CH2Nþ); 3.08–3.12 (2H, m,
CH2CvNþ); 3.51 (2H, t, J¼7.30 Hz, CH2CH2CvNþ);
4.10–4.13 (2H, m, CH2Nþ); 4.49 (2H, t, J¼7.92 Hz,
CH2CH2Nþ). 13C NMR (68 MHz, CDCl3): d 19.14 (CH2-
CH2CH2CvNþ); 21.40; 24.19 and 28.79 ((CH2)3CH2-
CvNþ); 31.23 (CH2CvNþ); 42.23 ((CH2)4CH2CvNþ);
52.88 (CH2Nþ); 63.93 ((CH2)4CH2Nþ). IR (NaCl, cm21):
1675 (nCvNþ).
3.1.12. 2,3,4,6,7,8,9,10-Octahydro-1H-pyrido[1,2-a]aze-
pinylium chloride 28. By heating compound 27 at 1158C
(oil bath) during 1 h a dark solid was obtained, which, after
washing with dry diethyl ether, yielded an orange salt, that
was further dried under high vacuum (0.01 mm Hg). Yield
1
79%. H NMR (270 MHz, CDCl3): d 1.68–1.80 (2H, m,
CH2CH2(CH2)3Nþ); 1.81–1.99 (6H, m, CH2(CH2)2CH2Nþ
and (CH2)2CH2(CH2)2Nþ); 2.00–2.11 (2H, m, (CH2)3-
CH2CH2Nþ); 3.00–3.14 (4H, m, 2£CH2CvNþ); 3.94–
4.04 (2H, m, (CH2)4CH2Nþ); 4.15–4.25 (2H, m, (CH2)3-
CH2Nþ). 13C NMR (68 MHz, CDCl3): d 16.84 (CH2(CH2)3-
Nþ); 20.92 ((CH2)3CH2CH2Nþ); 21.51 ((CH2)2CH2(CH2)2-
Nþ); 23.90 ((CH2)2CH2CH2Nþ); 28.75 (CH2CH2(CH2)2-
Nþ); 35.09 (CH2(CH2)3Nþ); 37.39 (CH2(CH2)4Nþ); 55.56
((CH2)4CH2Nþ); 59.71 ((CH2)3CH2Nþ); 193.56 (CvNþ).
IR (NaCl, cm21): 1675 (nCvNþ).
3.1.8. 1,2,3,4,6,7,8,9-Octahydro-quinolizinylium chloride
1
20. Yield 85%, yellow–orange salt. H NMR (270 MHz,
CDCl3): d 1.88–1.97 (4H, m, 2£CH2CH2CvNþ); 2.04–
2.12 (4H, m, 2£CH2CH2NþvC); 2.79–3.03 (4H, m,

K. Abbaspour Tehrani et al. / Tetrahedron 59 (2003) 3099–3108
3105
3.1.13. 6-(6-Chlorohexyl)-2,3,4,5-tetrahydropyridine 31.
Yield 93%, colorless liquid. 1H NMR (270 MHz, CDCl3): d
1.28–1.61 (8H, m, Cl(CH2)2(CH2)3 and NCH2CH2); 1.62–
1.73 (2H, m, N(CH2)2CH2); 1.78 (2H, quint, J¼7.42 Hz,
ClCH2CH2); 2.07–2.19 (4H, m, 2£CH2CvN); 3.49–3.59
(4H, m, ClCH2 and NCH2). 13C NMR (68 MHz, CDCl3): d
19.57; 21.89; 26.20 and 28.68 (NCH2(CH2)2 and Cl(CH2)3-
(CH2)2); 26.70 (Cl(CH2)2CH2); 29.09 (CH2CvN); 32.49
(ClCH2CH2); 40.83 (CH2CvN); 45.07 (ClCH2); 49.09
(NCH2); 171.19 (CvN). IR (NaCl, cm21): 1663 (nCvN).
MS (70 eV): m/z (%): 201/3 (Mþ, 3); 166 (17); 152 (2); 138
(3); 124 (8); 110 (19); 98 (12); 97 (100); 96 (23); 82 (7); 69
(6); 55 (8). Purity: 99% (GC). Anal. calcd for C11H20ClN: C
65.49%; H 9.99%; N 6.94%. Found: C 65.62%; H 10.08%;
N 7.03%.
(5£CH2); 54.09 (CH2N); 60.79 (CH2N); 64.15 (CHN).
Other isomer (recognizable signals): 18.80; 20.74; 26.47;
28.54; 30.37; 54.81; 59.12; 65.05. IR (NaCl, cm21):
nmax¼2850; 2730; 1615; 1425; 1360; 1323; 1252; 1105;
998; 807. MS (70 eV): m/z (%): 139 (Mþ, 45); 138 (100);
124 (17); 111 (34); 110 (27); 97 (16); 96 (20); 84 (13); 83
(40); 82 (12); 70 (19); 69 (17); 68 (9); 55 (14); 43 (9); 41
(25). Anal. calcd for C9H17N: C 77.63%; H 12.31%; N
10.06%. Found: C 77.51%; H 12.39%; N 10.13%.
3.2.4. cis- and trans-5-Methylindolizidine 11. Yield 68%,
colorless liquid. Bp (mixture of cis and trans) 62–678C/
13 mm Hg. Both diastereomers were separated by prepara-
tive gas chromatography (temperature column 1108C, cis/
trans 75/25). Spectral data are in accordance with the
1
literature.54 cis-11: H NMR (270 MHz, CDCl3): d 1.11
3.2. General procedure for the reduction of iminium
salts
(3H, d, J¼6.27 Hz, Me); 1.17–1.87 (10H, m); 1.80–1.85
(1H, overlap, m, CHN); 1.97 (1H, q, J¼8.91 Hz, (He)CHaN);
1.96–2.03 (1H, overlap, m, MeCH); 3.24 (1H, t£d, J¼8.58,
1.98 Hz, (He)CHaN). 13C NMR (68 MHz, CDCl3): d 20.23;
24.73; 30.57; 31.05; 34.30 (5£CH2); 21.13 (Me); 51.77
(CH2N); 58.92 (MeCH); 64.80 (CHN). IR (NaCl, cm21):
nmax¼2930; 2770; 2700; 2593; 1451; 1370; 1329; 1318; 1230;
1182; 1131; 1070. MS (70 eV): m/z (%): 139 (Mþ, 22); 138
(17); 124 (100); 111 (15); 110 (20); 96 (35); 70 (17); 49 (20);
As an example the reduction of 1,2,3,4,6,7,8,9-octahydro-
quinolizinylium chloride 20 is given. To 1.74 g (0.01 mol)
of quinolizidinium chloride 20, suspended in 20 mL of dry
diethyl ether, was added slowly at 08C 0.76 g (0.02 mol) of
LiAlH4. After heating 3 h under reflux water (3 mL) was
added at 08C in order to neutralize the excess of LiAlH4. The
mixture was stirred for 10 min after which the grey
suspension was filtered over K2CO3 and celite. The filter
cake was then washed thoroughly with dry ether (3£25 mL).
After removal of the solvent in vacuo, the colorless
quinolizidine 21 was obtained in 70% yield (purity
.97%, GC).
1
42 (20); 41 (29); 40 (84). trans-11: H NMR (270 MHz,
CDCl3): d 0.97 (3H, d, J¼6.60 Hz, Me); 1.09–1.86 (10H, m);
2.38–2.49 (1H, m, CHN); 2.54 (1H, q, J¼8.8 Hz, (He)CHaN);
2.81(1H, t£d, J¼8.7, 2.97 Hz, (He)CHaN); 3.19–3.30(1H, m,
MeCH). 13C NMR (68 MHz, CDCl3): d 9.28 (Me); 19.32;
20.81; 30.55; 31.46; 31.57 (5£CH2); 49.15 (CH2N); 49.97
(MeCH); 54.52 (CHN). IR (NaCl, cm21): nmax¼2925; 2793;
1460; 1370; 1339; 1262; 1172; 1151; 1092; 1077; 1022; 992;
840. MS (70 eV): m/z (%): 139 (Mþ, 22); 138 (16); 125 (14);
96 (20); 88 (20); 86 (43); 84 (64); 51 (20); 49 (76); 44 (15); 41
(24); 40 (100).
3.2.1. 1-Azabicyclo[4.4.0]decane 21. Spectral data are in
accordance with the literature, but are annotated in more
detail.17 1H NMR (270 MHz, CDCl3): d 1.12–1.36 (4H, m,
2£NCH2CH2CH2); 1.44–1.81 (9H, m, 2£NCH2CH2,
2£CHCH2, NCH); 1.88–2.06 (2H, m, 2£NHC(H)); 2.72–
2.84 (2H, m, 2£NHC(H)). 13C NMR (68 MHz, CDCl3): d
24.64 (2£CH2CH2CH2); 25.89 (2£NCH2CH2); 33.46
(2£CH2CH); 56.66 (2£CH2N); 63.00 (CHN). IR (NaCl,
cm21): n¼3359. MS (70 eV): m/z (%): 139 (Mþ, 48); 138
(100); 124 (12); 111 (15); 110 (43); 98 (10); 97 (68); 96
(16); 83 (57); 82 (16); 69 (7); 56 (5); 55 (22); 54 (6); 42 (7);
41 (11).
3.2.5. cis- and trans-8-(2-Propenyl)indolizidine 14. Yield
84% (mixture of cis and trans), yellow liquid. Both
diastereomers were separated by preparative gas chroma-
tography (temperature column 1108C, cis/trans 35/65 or
vice versa). cis- or trans-14: 1H NMR (270 MHz, CDCl3): d
0.80 (1H, q£d, J¼12.26, 5.07 Hz, NCH(HCH) or
NCHCH(HCH)); 1.16–2.18 (13H, m, N(HCH)CH2-
(HCH)CH(CH2CHvCH2) and NCH(CH2)2(HCH) or
N(HCH)(CH2)2CH(CH2CHvCH2) and NCH(HCH)CH2-
(HCH)); 2.92–3.03 (2H, m, 2£N(HCH)); 4.85–4.97 (2H,
m, CH2vCH); 5.61–5.78 (1H, m, CH2vCH). 13C NMR
(68 MHz, CDCl3): d 19.78; 24.78; 28.36; 29.34 and 37.25
(NCH2(CH2)2CH(CH2CHvCH2) and NCH2(CH2)2CH);
40.90 (N(CH2)3CH(CH2CHvCH2)); 52.00 and 53.75
(2£NCH2); 68.37 (NCH); 115.02 (CH2vCH); 136.06
(CH2vCH). IR (NaCl, cm21): nmax¼3076; 2961; 2929;
2781; 2719. MS (70 eV): m/z (%): 165 (Mþ, 16); 164 (27);
136 (76); 124 (32); 123 (100); 122 (55); 97 (30); 96 (52); 84
(21); 83 (25); 69 (28). trans- or cis-17: 1H NMR (270 MHz,
CDCl3): recognizable signals from a mixture of cis and
trans: d 2.61–2.68 (m) and 2.81–2.89 (m). 13C NMR
(68 MHz, CDCl3): d 19.96; 20.31; 24.71; 26.65 and 30.35
(NCH2(CH2)2CH(CH2CHvCH2) and NCH2(CH2)2CH);
34.23 (N(CH2)3CH(CH2CHvCH2)); 52.85 and 54.27
(2£NCH2); 66.22 (NCH); 114.46 (CH2vCH); 137.73
(CH2vCH). MS (70 eV): m/z (%): 165 (Mþ, 16); 164
3.2.2. d-Conice¨ıne 7. Yield 59%, colorless liquid. The
spectrometric data of indolizidine are in accordance with the
literature data.36,47 1H NMR (270 MHz, CDCl3): d 1.15–
1.33 (2H, m); 1.34–1.52 (1H, m); 1.53–1.88 (8H, m);
1.90–2.10 (2H, m); 3.00–3.11 (2H, m). 13C NMR (68 MHz,
CDCl3): d 20.70; 24.64; 25.62; 30.58; 31.21 (5£CH2); 53.15
and 54.38 (2£CH2N); 64.42 (CHN).
3.2.3. 6-Methylindolizidine 9. Yield 68%, colorless liquid.
Bp (mixture of cis and trans) 61–688C/12 mm Hg. An
analytical pure sample of one diastereomer could be
obtained by preparative gas chromatography (temperature
1
column 1108C, cis/trans 10/90 or vice versa). H NMR
(270 MHz, CDCl3): d 0.88 (3H, d, J¼6.27 Hz, MeCH);
1.14–1.94 (11H, m); 2.04 (1H, q, J¼8.91 Hz, (H)CHN);
2.99–3.07 (2H, m, 2£(H)CHN). Other isomer (recognizable
signals): 1.10 (d, J¼7.26 Hz, MeCH). 13C NMR (68 MHz,
CDCl3): d 19.55 (Me); 21.11; 30.22; 30.85; 31.27; 33.69

3106
K. Abbaspour Tehrani et al. / Tetrahedron 59 (2003) 3099–3108
(24); 136 (68); 124 (32); 123 (100); 122 (51); 97 (36); 96
(61); 84 (24); 83 (26); 69 (33). Anal. calcd for C11H19N: C
79.94%; H 11.59%; N 8.47%. Found: C 79.77%; H 11.51%;
N 8.62%.
signals from a mixture of cis and trans: d 1.00 (3H, d,
J¼6.60 Hz, CH3). MS (70 eV): m/z (%): 153 (Mþ, 13); 152
(11); 138 (100); 124 (5); 110 (12); 97 (7); 96 (5); 83 (7); 55 (7).
3.2.9. 1-Azabicyclo[5.4.0]undecane 29. Yield 69%, yellow
liquid. 1H NMR (270 MHz, CDCl3): d 1.17–1.88 (14H, m,
NCH2(CH2)4CH(CH2)3CH2); 1.91–2.02 (1H, m, CH);
2.17–2.28 (1H, m, N(HCH)); 2.38–2.52 (1H, m,
N(HCH)); 2.66–2.76 (1H, m, N(HCH)); 2.78–2.87 (1H,
m, N(HCH)). 13C NMR (68 MHz, CDCl3): d 24.60; 24.94;
26.13; 26.85 and 27.15 (NCH2(CH2)3CH2CHCH2(CH2)2-
CH2); 34.48 and 35.47 (2£NCHCH2); 57.45 and 57.50
(2£NCH2); 65.66 (CH). IR (NaCl, cm21): nmax¼2934;
2858; 2808; 1445; 908. MS (70 eV): m/z (%): 153 (Mþ, 41);
152 (29); 124 (63); 111 (34); 110 (100); 97 (53); 96 (27); 83
(30); 69 (16); 55 (20). Anal. calcd for C10H19N: C 78.37%; H
12.50%; N 9.14%. Found: C 78.57%; H 12.59%; N 9.07%.
3.2.6. 1-Azabicyclo[5.3.0]decane 17. Yield 78%, colorless
1
liquid. H NMR (270 MHz, CDCl3): d 1.2–2.1 (12H, m,
6£CH2); 2.2–2.4 (4H, m, 2£CH2N); 2.9–3.1 (1H, m,
CHN). 13C NMR (68 MHz, CDCl3): d 22.89; 26.01; 26.27;
28.37; 33.60; 35.17 (6£CH2); 55.63 (CH2N); 57.88 (CH2H);
65.39 (CHN). IR (NaCl, cm21): nmax¼2793; 2697; 1417;
1362; 1325; 1280; 1205; 775; 757. MS (70 eV): m/z (%):
139 (Mþ, 33); 138 (25); 124 (8); 111 (10); 110 (40); 97 (39);
96 (100); 84 (15); 83 (61); 82 (15); 70 (12); 69 (12); 67 (6);
56 (6); 55 (26); 54 (8); 42 (18). Anal. calcd for C9H17N: C
77.63%; H 12.31%; N 10.06%. Found: C 77.79%; H
12.45%; N 9.96%.
3.2.7. cis- and trans-4-Methylquinolizidine 25. Yield 96%
(mixture of cis and trans), yellow liquid. The trans-
diastereomer was separated by preparative gas chromato-
graphy (temperature column 1108C, cis/trans 15/85).
trans-25: 1H NMR (270 MHz, CDCl3): d 0.84 (3H, d,
J¼5.93 Hz, CH3); 1.17–1.37 and 1.49–1.81 (13H, 2£m,
N(HCH)CH(Me)(CH2)2CH(CH2)3); 1.89–2.03 (1H, m,
N(HCH)CH2); 2.68–2.84 (2H, m, N(HCH)CH2 and
N(HCH)CH(Me)). 13C NMR (68 MHz, CDCl3): d 19.77
(CH3); 24.69; 25.86 and 33.35 (N(CH2)2(CH2)CHCH2);
31.23 (CH(Me)); 33.21 and 33.49 (NCH2CH(Me)CH2 and
NCH2CH2); 56.59 (NCH2CH2); 62.50 (CHN); 64.46
(NCH2CH(Me)). IR (NaCl, cm21): nmax¼2929; 2865;
2853; 2799; 2763; 1456; 1375; 1122. MS (70 eV): m/z
(%): 153 (Mþ, 44); 152 (100); 138 (16); 124 (33); 111 (30);
110 (13); 98 (10); 97 (44); 96 (15); 84 (12); 83 (31); 82 (15);
69 (5); 55 (18). Anal. calcd for C10H19N: C 78.37%; H
12.50%; N 9.14%. Found: C 78.22%; H 12.61%; N 9.24%.
3.3. General procedure for the reduction of cyclic imines
As an example, the reduction of imine 27 is described. To a
solution of 0.19 g (0.001 mol) of 6-(5-chloropentyl)-2,3,4,5-
tetrahydropyridine 27 in 5 mL of methanol was added
0.08 g (0.002 mol) of NaBH4 at 08C. After heating 4 h at
reflux the reaction mixture was poured into 20 mL of 0.5 M
NaOH solution. Extraction with diethyl ether (2£30 mL,
1£20 mL), drying with K2CO3 and evaporation of the
solvent yielded 0.17 g of a colorless liquid in which 71%
piperidine 30 and 29% bicyclic amine 29 was present
(GC-MS).
3.3.1. 2-(5-Chloropentyl)piperidine 30. Colorless liquid.
1H NMR (270 MHz, CDCl3): d 0.96–1.13 (1H, m,
(HCH)(CH2)4Cl); 1.23–1.71 (11H, m, (CH2)3CH2N and
(HCH)(CH2)2(CH2)2Cl); 1.77 (2H, quint, J¼6.85 Hz, CH2-
CH2Cl); 2.37–2.50 (1H, m, CH); 2.62 (1H, t£d, J¼11.71,
2.86 Hz, (HCH)N); 3.01–3.11 (1H, m, (HCH)N); 3.53 (2H,
t, J¼6.77 Hz, CH2Cl). 13C NMR (68 MHz, CDCl3): d
24.87; 25.16; 26.65; 27.06 and 37.30 ((CH2)3CH2N and
CH2(CH2)2(CH2)2Cl); 32.52 (CH2CH2Cl); 32.97 (CH2-
(CH2)4Cl); 45.03 (CH2Cl); 47.22 (CH2N); 56.75 (CH). IR
(NaCl, cm21): 3276 (nNH); nmax¼2930; 2855; 2797; 1443.
MS (70 eV): m/z (%): 189 (Mþ, 1); 154 (3); 153 (3); 125 (4);
110 (7);86(14); 84(100);57(5);56(7);55(5);51(5);49(16).
1
cis-25: H NMR (270 MHz, CDCl3): recognizable signals
from a mixture of cis and trans: d 1.11 (3H, d, J¼7.26 Hz,
CH3); 2.09–2.16 (1H, m); 2.50–2.56 (1H, m); 2.63–2.68
(1H, m). 13C NMR (68 MHz, CDCl3): d 18.29 (CH3); 25.59;
28.41; 28.55; 30.04; 30.94 and 32.85 (NCH2(CH2)3-
CH(CH2)2CH(Me)CH2); 56.96 (NCH2CH(Me)); 61.99
(CHN); 63.43 (NCH2CH2). MS (70 eV): m/z (%): 153
(Mþ, 41); 152 (100); 138 (21); 125 (12); 124 (35); 111 (35);
110 (17); 98 (10); 97 (45); 96 (15); 86 (34); 84 (58); 83 (33);
82 (20); 69 (7); 55 (21); 49 (26).
3.3.2. 2-(6-Chlorohexyl)piperidine 33. Yield 87%, color-
less liquid. 1H NMR (270 MHz, CDCl3): d 0.96–1.70 (14H,
m, Cl(CH2)2(CH2)4 and CH(CH2)3CH2N); 1.77 (2H, quint,
J¼7.09 Hz, ClCH2CH2); 2.36–2.48 (1H, m, CHN); 2.62
(1H, t£d, J¼11.63, 2.86 Hz, (HCH)N); 3.01–3.11 (1H, m,
(HCH)N); 3.53 (2H, t, J¼6.77 Hz, CH2Cl); NH invisible.
13C NMR (68 MHz, CDCl3): d 24.91; 25.73; 26.65; 26.83;
29.09; 32.99 and 37.38 ((CH2)3CH2N and (CH2)4(CH2)2Cl);
32.58 (CH2CH2Cl); 45.10 (CH2Cl); 47.24 (CH2N); 56.82
(CH). IR (NaCl, cm21): 2928 (nNH); nmax¼2855; 2797;
2737; 1443; 1328; 1310; 1122. MS (70 eV): m/z (%): 203/5
(Mþ, 5); 168 (3); 140 (2); 112 (2); 85 (17); 84 (100); 56 (12);
49 (6). Purity: 99% (GC).
3.2.8. cis- and trans-3-Methylquinolizidine 23. Yield 97%
(mixture of cis and trans), yellow liquid. The cis-
diastereomer was separated by preparative gas chromato-
graphy (temperature column 1108C, cis/trans 60/40). cis-23:
1H NMR (270 MHz, CDCl3): d 1.10 (3H, d, J¼6.27 Hz,
CH3); 1.18–1.82 and 1.87–2.05 (14H, 2£m, NCH(Me)-
(CH2)3CH(CH2)3(HCH)); 1.87–2.05 (1H, m, NCH(Me));
3.20–3.31 (1H, m, N(HCH)). 13C NMR (68 MHz, CDCl3):
d 20.74 (CH3); 24.53; 24.67; 26.29; 33.84; 34.05 and 35.31
(NCH2(CH2)3 and NCH(Me)(CH2)3); 51.77 (CH2N); 59.07
(NCH(Me)); 63.05 (CHN). IR (NaCl, cm21): nmax¼2961;
2928; 2857; 2784; 2745; 1644; 1444. MS (70 eV): m/z (%):
153 (Mþ, 12); 152 (14); 138 (100); 124 (6); 110 (14); 97 (7);
96 (5); 83 (9); 55 (10). Anal. calcd for C10H19N: C 78.37%;
H 12.50%; N 9.14%. Found: C 78.24%; H 12.58%; N
9.08%. trans-23: 1H NMR (270 MHz, CDCl3): recognizable
3.4. Synthesis of quinolizidine-9a-carbonitrile 26
To 0.45 g (26 mmol) of quinolizidinium chloride 20,
dissolved in 10 mL of a 1:1 mixture of methanol:

K. Abbaspour Tehrani et al. / Tetrahedron 59 (2003) 3099–3108
3107
16. Reinecke, M. G.; Kray, L. R. J. Org. Chem. 1964, 29,
1736–1739.
tetrahydrofuran, was added at room temperature 0.34 g
(52 mmol) of potassium cyanide. This mixture was stirred
during 15 h at room temperature after which it was poured
in 15 mL of water and extracted with diethyl ether
(3£20 mL). Drying of the organic phase (MgSO4) and
removal of the solvent in vacuo afforded 0.33 g (77%) of
compound 26 as a light-yellow liquid.
17. Yamaguchi, R.; Nakazono, Y.; Matsuki, T.; Hata, E. Bull.
Chem. Soc. Jpn 1987, 60, 215–222.
18. Ojima, I.; Iula, D. M.; Tzamarioudaki, M. Tetrahedron Lett.
1998, 39, 4599–4602.
19. Edwards, P. D.; Meyers, A. I. Tetrahedron Lett. 1984, 25,
939–942.
3.4.1. 6-Cyano-1-azabicyclo[4.4.0]decane 26. 1H NMR
(270 MHz, CDCl3): d 1.43–1.78 (10H, m, 2£NCH2-
(CH2)2(HCH)); 1.79–1.91 (2H, m, 2£(HCH)CCN); 2.28–
2.43 (2H, m, 2£(HCH)N); 2.62–2.73 (2H, m, 2£(HCH)N).
13C NMR (68 MHz, internal standard CDCl3): d 20.88 and
24.46 (2£NCH2(CH2)2); 36.28 (2£CH2CCN); 51.79
(2£CH2N); 60.49 (CCN); 117.27 (CN). IR (NaCl, cm21):
2216 (nCN); nmax¼2935; 2863; 2817; 2768; 1642; 1446;
1355; 1291; 1117. It was not possible to obtain a correct
mass spectrum of this compound due to its lability.
20. Khatri, N. A.; Schmitthenner, H. F.; Shringarpure, J.; Weinreb,
S. M. J. Am. Chem. Soc. 1981, 103, 6387–6393.
21. Padwa, A.; Heidelbaugh, T. M.; Kuethe, J. T. J. Org. Chem.
2000, 65, 2368–2378.
22. Pearson, W. H.; Lin, K.-C. Tetrahedron Lett. 1990, 31,
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¨
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