A one-pot assembly of 4-allyl-3-pyridinecarboxaldehyde. A new synthesis of 1-methyl-1,2,3,3a,4,8b-hexahydropyrrolo[3,2-f]pyrindine, an annulated nicotine analogue

Article abstract of DOI:10.1016/j.tet.2004.04.069

This paper describes a two-step synthesis of 1-methyl-1,2,3,3a,4,8b- hexahydropyrrolo[3,2-f]pyrindine, a conformationally constrained nicotine analogue. The target molecule was effectively assembled by an intramolecular azomethine ylide-alkene [3+2] cycloaddition. The cyclization precursor, 4-allyl-3-pyridinecarboxaldehyde, was formed efficaciously in a single step from 3-pyridinecarboxaldehyde via sequential in situ protection, ortho lithiation, cuprate formation, allylation, and deprotection. The cuprate formation plays a vital role in minimizing/eliminating the extent of multiple alkylation.

Full text of DOI:10.1016/j.tet.2004.04.069

Tetrahedron 60 (2004) 5353–5355
A one-pot assembly of 4-allyl-3-pyridinecarboxaldehyde.
A new synthesis of
1-methyl-1,2,3,3a,4,8b-hexahydropyrrolo[3,2-f]pyrindine,
an annulated nicotine analogue
Shengjun Luo,a Fang Fang,a Mingyue Zhaob and Hongbin Zhaia
,
*
aLaboratory of Modern Synthetic Organic Chemistry and State Key Laboratory of Bio-Organic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
bZhengzhou Tobacco Research Institute, Zhengzhou, Henan 450000, China
Received 8 March 2004; revised 22 April 2004; accepted 23 April 2004
Abstract—This paper describes a two-step synthesis of 1-methyl-1,2,3,3a,4,8b-hexahydropyrrolo[3,2-f]pyrindine, a conformationally
constrained nicotine analogue. The target molecule was effectively assembled by an intramolecular azomethine ylide-alkene [3þ2]
cycloaddition. The cyclization precursor, 4-allyl-3-pyridinecarboxaldehyde, was formed efficaciously in a single step from
3-pyridinecarboxaldehyde via sequential in situ protection, ortho lithiation, cuprate formation, allylation, and deprotection. The cuprate
formation plays a vital role in minimizing/eliminating the extent of multiple alkylation.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
activity despite of its toxicity.5 On the other hand, molecular
modeling studies have demonstrated that the two hetero-
cyclic rings of nicotine are skewed and approximately
perpendicular to one another to secure low energy
conformations.3,6
(2)-Nicotine (1, Fig. 1), an alkaloid present in tobacco at
0.2–5% levels, targets and activates nicotinic acetylcholine
receptors (nAChRs).1 The nAChRs provide ligand-gated
ion channels in the human brain and participate in various
biological processes related to numerous nervous system
disorders.2 Due to the therapeutic potential of (2)-nicotine
for central nervous system (CNS) disorders such as
Alzheimer’s, Parkinson’s, and Tourette’s diseases, nicotine
analogues have received much attention from both synthetic
and medicinal chemists.2 In particular, conformationally
constrained nicotinoids have become attractive candidates
for new selective nAChRs-targeting ligands.2a,3,4 On one
hand, this is because of the discovery of epibatidine, an
alkaloid with a rigid structure, which displays strong
Our laboratory has been fascinated in the chemistry of
nicotine analogues aimed to develop new selective
nAChRs-targeting ligands. A tricyclic nicotine analogue,
1-methyl-1,2,3,3a,4,8b-hexahydropyrrolo[3,2-f]pyrindine
(2, Fig. 1), was previously designed and synthesized in six
steps from 3-bromopyridine.4b The conformational rigidity
of 2 was achieved as a result of a methylene bridge erected
between C-4 and C-50 of nicotine (1).
2. Results and discussion
Herein we wish to report a new synthesis of 2 with high
efficiency, featuring the construction of the hexahydro-
pyrrolo[3,2-f]pyrindine tricyclic framework via intra-
molecular azomethine ylide-alkene [3þ2] cycloaddition.4b,7
The apparent precursor for the cycloaddition would be
4-allyl-3-pyridinecarboxaldehyde (3, Fig. 2), whose effi-
cient synthesis itself represents one of the challenges for the
current project. In principle, aldehyde 3 might be obtainable
from 4-allyl-3-bromopyridine (4) by sequential treatment
with BuLi and N,N-dimethylformamide (DMF). Alkene 4
was reportedly8 synthesized from 3-bromopyridine in only
Figure 1.
Keywords: Annulated nicotine analogue; Intramolecular azomethine ylide-
alkene [3þ2] cycloaddition; Synthesis.
*
Corresponding author. Tel.: þ86-21-64163300; fax: þ86-21-64166128;
e-mail address: zhaih@mail.sioc.ac.cn
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.04.069

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S. Luo et al. / Tetrahedron 60 (2004) 5353–5355
the four plausible intermediates). We have not been able to
further optimize this reaction so far. However, the current
protocol should be acceptable considering the fact that such
a useful intermediate as 3 can be assembled in a one-pot
fashion. The absence of CuCN resulted simply in a complex
reaction mixture because 3D (an 4-allylpyridine derivative)
was prone to further allylation due to the presence of the
highly acidic benzylic/allylic hydrogens. Replacement of
CuCN with CuBr led to less satisfactory results.
Figure 2.
40% yield. The unsatisfactory yield for this transformation
resulted mainly from the further alkylatability because of
the enhanced acidity of the benzylic hydrogens. By the same
token, the conversion of 4 to 3 could not be a clean reaction.
Having the enal in hand set the stage for intramolecular
azomethine ylide-alkene [3þ2] cycloaddition.7 Treatment4b
of 3 with sarcosine (120 mol%) in DMF at 120 8C for 5 h
effected the desired cycloaddition (see the transition state
2A) to produce in 86% yield the tricycle 2, an annulated
nicotine analogue. The spectroscopic data of the sample
were in accord with those reported previously.4b Currently
pharmacological studies of 2 are under way.
Ortho lithiation of aromatic aldehydes with prior in situ
aldehyde protection, first introduced by Comins and
co-workers,9 has proved to be a convenient and versatile
technique having considerable potential in organic
synthesis.10 We envisaged that this protocol might be
modified to synthesize enal 3 by a one-pot reaction from
3-pyridinecarboxaldehyde (5, Scheme 1). Indeed, the
desired 4-allyl-3-pyridinecarboxaldehyde 3 was afforded
when aldehyde 5 was protected in situ with LTMDA
[Me2N(CH2)2N(Li)Me, prepared by mixing N,N,N0-tri-
methylethylenediamine and n-BuLi], ortho lithiated with
n-BuLi, converted to a high-order cuprate with CuCN,
alkylated with allyl bromide, and finally hydrolyzed. The
yield for this step was 44%, which amounted to an average
yield of 85% for each of the five operations (3A–3D were
3. Conclusion
In summary, a two-step synthesis of 1-methyl-1,2,3,3a,4,8b-
hexahydropyrrolo[3,2-f]pyrindine (2), a conformationally
constrained nicotine analogue, has been accomplished. The
target molecule was effectively assembled by an intramo-
lecular azomethine ylide-alkene [3þ2] cycloaddition. The
cyclization precursor, 4-allyl-3-pyridinecarboxaldehyde (3),
was formed efficaciously in a single step from 3-pyridine-
carboxaldehyde (5) via sequential in situ protection, ortho
lithiation, cuprate formation, allylation, and deprotection.
The cuprate formation plays a vital role in minimizing/
eliminating the extent of multiple alkylation.
4. Experimental
4.1. General
NMR spectra were recorded in CDCl3 (1H at 300 MHz and
13C at 75.47 MHz), using TMS as the internal standard
when appropriate. Column chromatography was performed
on silica gel. THF were distilled over sodium benzophenone
ketyl under N2 prior to use. DMF was distilled over calcium
hydride under N2 prior to use.
4.1.1. 4-Allyl-3-pyridinecarboxaldehyde (3). n-BuLi
(2.08 M, 05.6 mL, 12 mmol) was added to a stirred solution
of N,N,N -trimethylethylenediamine (1.62 mL, 12.5 mmol)
in THF (40 mL) at 278 8C. After 15 min, 3-pyridinecar-
boxaldehyde (1.0 mL, 10.6 mmol) was added at 278 8C,
and the stirring was continued for 15 min. n-BuLi (2.08 M,
10 mL, 21 mmol) was added at 278 8C and the stirring was
continued at 242 8C for 3 h. After cooling to 278 8C,
CuCN (1.99 g, 22.2 mmol) was added as a solid and the
temperature was maintained at 240 8C for 2 h and then at
230 8C for 1 h. After cooling to 278 8C, a solution of allyl
bromide (1.9 mL, 22 mmol) in THF (10 mL) was added at
278 8C. The reaction mixture was allowed to warm to rt,
diluted with saturated aqueous Na2SO3 and saturated
aqueous NaHCO3, and extracted with EtOAc. The com-
bined organic layers were dried (Na2SO4), filtered, and
concentrated. The residue was purified by column
Scheme 1.

S. Luo et al. / Tetrahedron 60 (2004) 5353–5355
5355
chromatography to afford 3 (686 mg, 44%) as a colorless
References and notes
oil: FT-IR (KBr, cm21): 2861, 2754, 1702, 1639, 1592,
1556, 1489, 1400, 1222, 1058, 997, 923, 839, 735, 690, 658;
1H NMR (CDCl3, 300 MHz) d 3.73 (d, 2H, J¼5.2 Hz), 4.97
(dd, 1H, J¼17.2, 2.8 Hz), 5.06 (dd, 1H, J¼10.5, 2.7 Hz),
5.81–5.96 (m, 1H), 7.18 (d, 1H, J¼4.8 Hz), 8.58 (d, 1H,
J¼4.8 Hz), 8.87 (s, 1H), 10.17 (s, 1H); 13C NMR (CDCl3,
75 MHz) d 35.9, 117.7, 125.2, 129.0, 134.3, 150.5, 153.6,
153.7, 191.2; MS (EI): 147 (Mþ, 30), 146 (M21, 100);
HRMS (EI) calcd for C9H9NO, 147.0684, found 147.0687.
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4.1.2. 1-Methyl-1,2,3,3a,4,8b-hexahydropyrrolo[3,2-
f]pyrindine (2). A mixture of aldehyde 3 (686 mg,
4.66 mmol) and sarcosine (495 mg, 5.56 mmol) in DMF
(40 mL) was heated under N2 at 120 8C for 5 h, cooled to rt,
and concentrated in vacuo. The residue was diluted with
saturated aqueous NaHCO3 solution and extracted with
isopropanol/CHCl3 (1/3). The combined organic layers
were dried over MgSO4, filtered, and concentrated. The
residue was chromatographed (SiO2, CH2Cl2–MeOH, 40/1)
1
to give 2 (700 mg, 86%) as a pale yellow oil: H NMR
(CDCl3, 300 MHz) d 1.62–1.74 (m, 1H), 2.15–2.25 (m,
1H), 2.44–2.55 (m, 1H), 2.55 (s, 3H), 2.77–2.86 (m, 1H),
2.99–3.21 (m, 3H), 3.80 (d, J¼7.6 Hz, 1H), 7.13 (d,
J¼5.2 Hz, 1H), 8.42 (d, J¼5.2 Hz, 1H), 8.60 (s, 1H); 13C
NMR (CDCl3, 75 MHz) d 32.23, 39.23, 40.50, 41.92, 57.59,
73.45, 120.34, 139.25, 145.78, 148.34, 152.95. MS (EI): 174
(Mþ). Anal. calcd for C11H14N2: C, 75.82; H, 8.10; N,
16.08. Found: C, 75.69; H, 7.84; N, 16.38.
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Acknowledgements
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We thank National Natural Science Foundation of China
(No. 20372073), The Bureau of Tobacco, PRC, and Science
and Technology Commission of Shanghai Municipality
(‘Venus’ Program) for financial support.