Concise synthesis of new bridged-nicotine analogues

Article abstract of DOI:10.1016/j.tet.2011.12.029

This study describes a very efficient strategy for the synthesis of two new bridged-nicotine analogues. Starting from either 4- or 3-chloropyridine the desired tricyclic ring systems are accessed in just three steps in 23% and 40% overall yield, respectively.

Full text of DOI:10.1016/j.tet.2011.12.029

Tetrahedron 68 (2012) 1417e1421
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Concise synthesis of new bridged-nicotine analogues
,
,
Franc¸ ois Crestey a, Geert Hooyberghs a b, Jesper L. Kristensen a
*
a Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
b Department of Chemistry, Katholieke Universiteit Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 October 2011
Received in revised form 26 November 2011
Accepted 12 December 2011
Available online 16 December 2011
This study describes a very efficient strategy for the synthesis of two new bridged-nicotine analogues.
Starting from either 4- or 3-chloropyridine the desired tricyclic ring systems are accessed in just three
steps in 23% and 40% overall yield, respectively.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Pyridine metallation
Bridged-nicotine analogue
SuzukieMiyaura cross-coupling reaction
Nicotinic acetylcholine receptor
Intramolecular reductive amination
1. Introduction
Ligands 1 and 2 lock nicotine in the ‘down’ position,2a whereas
compound 3 locks nicotine in the ‘up’ position. Surprisingly, the
The nicotinic acetylcholine receptors (nAChRs) are ligand-gated
ion channels belonging to the Cys-loop receptor family. The in-
volvement of nAChRs in a wide range of diseases as well as neu-
rodegenerative and psychiatric disorders has made this class of
receptors a popular target for drug discovery.1 During the last de-
cades, structural modifications of nicotine have been the starting
point for many drug discovery programs.2 Introduction of confor-
mational restraint to flexible lead molecules is a tried and tested
approach in the development of new ligands and nicotine is no
exception. Thus, the constrained nicotine scaffolds 1,3 24 and 35 in
Fig. 1 have provided new and interesting pharmacological tools.6
direct analogue of nicotine locked in the ‘up’ position, i.e., com-
pound 4 has not yet been described in the literature. Herein we
report a very efficient synthesis of this novel bridged-nicotine an-
alogue and the application of this approach to an isomeric ring
system using the same methodology.
The first synthetic strategy towards 4 from the three commer-
cially available building blocks 5e7 is outlined in Fig. 2. ortho-
Lithiation of 4-chloropyridine hydrochloride (5) and subsequent
trapping with N-Boc-pyrrolidinone 6,7 followed by formation of the
pyrrolidine moiety via intramolecular reductive amination,
a SuzukieMiyaura cross-coupling reaction with vinylboronic ester
78 and finally a second reductive amination should deliver the
tricyclic ring system.
Fig. 2. Retrosynthetic analysis.
2. Results and discussion
Fig. 1. Structure of nicotine and selected conformational restricted analogues.
* Corresponding author. E-mail address: jekr@farma.ku.dk (J.L. Kristensen).
For the synthesis of the desired 3,4-disubstituted pyridine 8, we
followed a modified procedure of the method recently published by
Jensen and co-workers.9 Starting material
5 was selectively
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.12.029

1418
F. Crestey et al. / Tetrahedron 68 (2012) 1417e1421
metallated at ꢀ78 ꢁC in dry THF with freshly prepared lithium
diisopropylamide (LDA) and subsequently quenched with pyrroli-
dinone 6 to give 4-chloropyridine 8 in 76% yield. After deprotection
of the Boc group in a mixture TFA/CH2Cl2 (1:1) at room tempera-
ture, the amine underwent an in situ cyclization resulting in the
formation of an imine, which was reduced to the corresponding
pyrrolidine using an excess of NaBH4. To ease purification and to
obtain a more suitable compound for the SuzukieMiyaura10 cross-
coupling reaction, the intermediate amine was protected with
(Boc)2O furnishing pyridine 9 in 71% yield on multigram scale over
three steps. NMR spectroscopy analysis of 9 showed the existence
of two rotamers at room temperature, which was in correlation
with the recent results published by Campos and co-workers on N-
Boc-pyrrolidine derivatives.11 The recent cross-coupling procedure
described by Whelligan and co-workers8 using boronic ester 7
(1.9 equiv), Pd(OAc) (3 mol %), SPhos12 (7 mol %) and K3PO4
(2 equiv) in a CH3CN/water (3:2) mixture was successfully applied
on our substrate under microwave (MW) conditions at 85 ꢁC for 3 h
providing pyridine 10 in 71% yield.13 Subsequent treatment in
a TFA/CH2Cl2 (1:1) mixture furnished an iminium salt intermediate,
which was reduced with an excess of NaBH4 in MeOH leading to
new bridged-nicotine analogue 4 in a four-step synthesis in 31%
overall yield (Scheme 1).
The synthesis of 4 via 11 is depicted in Scheme 3. Pyridine 5 was
ortho-lithiated with LDA (2.5 equiv) and subsequently quenched
with a slight excess of 6. After work-up the crude material was
immediately employed in the SuzukieMiyaura cross-coupling re-
action with vinylboronic 7 at 85 ꢁC for 70 min under MW condi-
tions giving 3,4-disubstituted pyridine 11 in 54% yield. Subsequent
treatment in TFA/CH2Cl2 (1:1) and reduction of the intermediate
with NaBH4 led to 4 in a three-step synthesis in 23% overall yield
(Scheme 3).
Scheme 3. Reagents and conditions: (i) (a) LDA (2.5 equiv), THF, ꢀ78 ꢁC; (b)
6
(1.3 equiv), ꢀ78 ꢁC to rt; (c) 7 (1.9 equiv), SPhos (6 mol %), Pd(OAc)2 (3 mol %), K3PO4
(2 equiv), CH3CN/water (3:2), MW, 85 ꢁC; (ii) (a) TFA/CH2Cl2 (1:1), 0 ꢁC to rt to 40 ꢁC;
(b) NaBH4 (5 equiv), MeOH, 0 ꢁC to rt; (iii) (a) LDA (1.2 equiv), THF, ꢀ78 ꢁC; (b) 6
(1.3 equiv), ꢀ78 ꢁC to rt; (c) 7 (1.9 equiv), SPhos (6 mol %), Pd(OAc)2 (3 mol %), K3PO4
(2 equiv), CH3CN/water (3:2), MW, 85 ꢁC.
To extend the scope of this methodology an isomeric naph-
thyridine ring 14 has been synthesized. Thus, after metallation of 3-
chloropyridine 12 and subsequent quenching with pyrrolidinone 6
the crude intermediate underwent
a SuzukieMiyaura cross-
coupling reaction in the presence of boronic ester 7 within 2 h
under MW conditions providing the 3,4-disubstituted pyridine 13
in 79% yield. Treatment in acidic media followed by reduction of the
iminium salt furnished the novel tricycle 14 in 40% overall yield
(Scheme 3).
Scheme 1. Reagents and conditions: (i) (a) LDA (2.5 equiv), THF, ꢀ78 ꢁC; (b)
6
(1.3 equiv), ꢀ78 ꢁC to rt; (ii) (a) TFA/CH2Cl2 (1:1), 0 ꢁC to rt; (b) NaBH4 (5 equiv), MeOH,
0
ꢁC to rt; (c) (Boc)2O (1.5 equiv), DMAP (0.2 equiv), TEA (1.5 equiv), CH2Cl2, rt; (iii) 7
3. Conclusion
(1.9 equiv), SPhos (7 mol %), Pd(OAc)2 (3.5 mol %), K3PO4 (2 equiv), CH3CN/water (3:2),
MW, 85 ꢁC; (iv) (a) TFA/CH2Cl2 (1:1), 0 ꢁC to rt; (b) NaBH4 (5 equiv), MeOH, 0 ꢁC to rt.
In summary, a mild and short method for the preparation of
a new bridged-nicotine analogue has been developed. This strategy
can allow the construction of novel substructures and building
blocks for applications in medicinal chemistry. Further studies
concerning the construction of new scaffolds are in progress in our
laboratories. The pharmacological evaluation of the new nicotine
derivatives 4 and 14 will be reported elsewhere in due course.
In an attempt to decrease the number of steps we investigated
another protocol in which a double intramolecular reductive ami-
nation from vinylpyridine 11 would form two rings in one step
(Scheme 2). This key intermediate 11 should be available via
a SuzukieMiyaura cross-coupling reaction of 8 with 7.
4. Experimental section
4.1. General
Starting materials and reagents were obtained from commercial
suppliers and used without further purifications. Syringes, which
were used to transfer anhydrous solvents or reagents were purged
with nitrogen prior to use. THF was continuously refluxed and
freshly distilled from sodium/benzophenone under nitrogen. Other
solvents were analytical or HPLC grade and were used as received.
n-BuLi was titrated following the procedure described by Burchat
and co-workers.14 Yields refer to isolated compounds estimated to
1
be >98% pure as determined by H NMR (25 ꢁC). Thin-layer chro-
matography (TLC) was carried out on silica gel 60 F254 plates from
Merck (Germany). Visualization was accomplished by UV lamp
(254 nm), or with either cemol dip with heat or iodine on silica as
an indicator. Flash column chromatography was performed on
Scheme 2. Proposed synthesis of 4 via one-pot double reductive aminaton from 11.
ꢀ
chromatography grade, silica 60 A particle size 35e70
m from Fisher

F. Crestey et al. / Tetrahedron 68 (2012) 1417e1421
1419
Scientific using the solvent system stated. 1H NMR and 13C NMR
spectra were recorded on Varian 300 (Mercury and Gemini) in-
struments, using CDCl3 as solvent and TMS as internal standard.
Coupling constants (J values) are given in hertz (Hz). Multiplicities
of 1H NMR signals are reported as follows: s, singlet; d, doublet; dd,
doublet of doublets; dt, doublet of triplets; t, triplet; q, quartet;
quint: quintet; m: multiplet; br s, broad signal. Microwave-assisted
synthesis was carried out in a Biotage Initiator apparatus operating
in single mode; the microwave cavity producing controlled irradi-
ation at 2.45 GHz (Biotage AB, Uppsala, Sweden). The reactions
were run in sealed vessels. These experiments were performed by
employing magnetic stirring and a fixed hold time using variable
power to reach (during 1e2 min) and then maintain the desired
temperature in the vessel for the programmed time period. The
temperature was monitored by an IR sensor focused on a point on
the reactor vial glass. The IR sensor was calibrated to internal so-
lution reaction temperature by the manufacturer. High-resolution
mass spectra (HRMS) were obtained using a Micromass Q-TOF 2
instrument and are all within 5 ppm of the theoretical values.
Melting points (mp) were measured using a MPA100 Optimelt
melting point apparatus and are uncorrected. The following ab-
breviations are used: PE: petroleum ether; THF: tetrahydrofuran;
TEA: triethylamine; Cp2ZrHCl: bis(cyclopentadienyl)zirconium(IV)
chloride hydride; SPhos: 2-(20,60-dimethoxybiphenyl)dicyclohex-
ylphosphine; (Boc)2O: di-tert-butyl dicarbonate; TFA: trifluoro-
acetic acid; DMAP: 4-dimethylaminopyridine; EtOAc: ethyl acetate.
The orange reaction mixture was stirred at ꢀ78 ꢁC for 1 h prior to the
addition of a solution of pyrrolidinone 6 (183 mg, 0.99 mmol,
1.3 equiv) in dry THF (1.5 mL) over 5 min. The resulting reaction
mixture was stirred at ꢀ78 ꢁC for 2 h then allowed to slowly warm up
to room temperature overnight. The resulting solution was quenched
with water and extracted with EtOAc (2ꢂ20 mL) then the combined
organic layers were washed with brine, dried over Na2SO4, filtered and
concentrated in vacuo. The crude material was purified by column
chromatography using Et2O/PE (20:1) as eluent to yield tert-butyl 4-
(4-chloropyridin-3-yl)-4-oxobutylcarbamate 8 (172 mg, 76%) as a pale
yellow oil; Rf¼0.45 (Et2O); 1H NMR (300 MHz):
d 8.70 (s, 1H), 8.55 (d,
J¼5.2,1H), 7.37 (d, J¼5.2,1H), 4.64 (br s,1H), 3.17e3.28 (m, 2H), 3.02 (t,
J¼6.9, 2H), 1.94 (quint, J¼6.9, 2H), 1.43 (s, 9H); 13C NMR (75 MHz):
d
207.8,156.2,152.3,150.1,141.4,134.7,125.6, 79.7, 40.6, 40.1, 28.9 (3C),
35
24.7; HRMS (EI): MNaþ, found 321.0984. C14
321.0982.
H ClN2O3 requires
19
4.1.4. tert-Butyl 2-(4-chloropyridin-3-yl)pyrrolidine-1-carboxylate
(9). To a solution of pyridine 8 (2.88 g, 9.64 mmol, 1 equiv) in
CH2Cl2 (20 mL) was added dropwise TFA (20 mL) at 0 ꢁC. The re-
action was allowed to warm up to room temperature and stirred at
this temperature for 3 h then basified by addition of a saturated
aqueous solution of K2CO3. The aqueous layer was extracted with
CH2Cl2 (5ꢂ70 mL) and the combined organic layers were washed
with brine, dried over Na2SO4, filtered and concentrated in vacuo.
The resulting material was dissolved in MeOH (40 mL) and cooled
to 0 ꢁC prior to the portionwise addition of NaBH4 (1.82 g,
48.20 mmol, 5 equiv). The reaction was allowed to warm up to
room temperature and stirred at this temperature for 1 h then
quenched by addition of an aqueous solution of HCl (1 M, 8 mL).
The reaction mixture was basified by addition of a saturated
aqueous solution of K2CO3 and extracted with CH2Cl2 (5ꢂ30 mL).
The combined organic layers were washed with brine, dried over
Na2SO4, filtered and concentrated in vacuo. The resulting crude
was taken up in CH2Cl2 (20 mL) then (Boc)2O (3.16 g, 14.46 mmol,
1.5 equiv), TEA (2.01 mL, 14.46 mmol, 1.5 equiv) and DMAP
(236 mg, 1.93 mmol, 0.2 equiv) were successively added at room
temperature. The reaction mixture was stirred at this temperature
for 14 h then washed with brine, dried over Na2SO4, filtered and
concentrated in vacuo. The crude material was purified by column
chromatography using EtOAc as eluent to give tert-butyl 2-(4-
4.1.1. N-tert-Butoxycarbonylpyrrolidinone (6)7b. To a solution of 2-
pyrrolidone (5.99 g, 70.38 mmol, 1 equiv) in CH3CN (130 mL)
were added successively (Boc)2O (18.43 g, 84.46 mmol, 1.2 equiv)
and DMAP (0.86 g, 7.04 mmol, 0.1 equiv) at room temperature. The
reaction mixture was stirred at this temperature for 14 h then the
solvent was removed in vacuo. The crude material was taken up in
EtOAc (100 mL) and washed with brine (100 mL). The organic layer
was dried over Na2SO4, filtered and concentrated in vacuo. The
resulting material was purified by column chromatography using
a gradient elution (EtOAc/PE, 1:1 to 2:1) to provide N-tert-butox-
ycarbonylpyrrolidinone 6 (11.01 g, 84%) as a pale yellow oil; Rf¼0.45
(Et2O/PE, 1:20); 1H NMR (300 MHz):
d
3.74 (t, J¼7.7, 2H), 2.51 (t,
J¼8.0, 2H), 2.00 (m, 2H), 1.94 (s, 9H); 13C NMR (75 MHz):
d 174.5,
150.3, 82.9, 46.7, 33.2, 28.3 (3C), 17.7.
chloropyridin-3-yl)pyrrolidine-1-carboxylate
9 (1.93 g, 71%) as
4.1.2. (E)-2-(2-Ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(7)8. To a cooled solution of ethoxyethyne (ca. 40% w/w solution in
hexanes, 5.69 g, 32.47 mmol, 1.3 equiv) in CH2Cl2 (70 mL) was
a yellow oil; the product was identified as a mixture of 2 rotamers
in a 1:1 ratio; Rf¼0.65 (EtOAc); 1H NMR (300 MHz):
d 8.29e8.39
(m, 2H), 7.25 (d, J¼5.2, 1H), 5.24 (br d, J¼7.2, 0.5H), 5.10 (dd, J¼7.7,
4.7, 0.5H), 3.60e3.72 (m, 1.5H), 3.46e3.59 (m, 0.5H), 2.28e2.47 (m,
1H), 1.75e1.98 (m, 3H), 1.45 (s, 4H), 1.19 (s, 5H); 13C NMR
added
4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(3.62 mL,
24.98 mmol, 1 equiv) at 0 ꢁC followed by Cp2ZrHCl (387 mg,
1.50 mmol, 0.06 equiv) under N2. After 5 min the reaction mixture
was allowed to warm up to room temperature and stirred at this
temperature for 16 h then solvents were removed in vacuo. The
crude material was purified by column chromatography using
a gradient elution (heptane/EtOAc, 9:1 to 8:1) to furnish (E)-2-(2-
(75 MHz):
d 154.4*, 154.1, 148.9*, 148.8, 148.5, 147.9*, 141.7, 137.9,
136.8*, 124.8*, 124.4, 80.2*, 80.0, 57.4, 57.3*, 47.7*, 47.4, 34.1, 32.9*,
28.8 (3C)*, 28.4 (3C), 23.7*, 23.6; *signal corresponding to the
35
minor rotamer; HRMS (EI): MHþ found 283.1230. C14
requires 283.1213.
H ClN2O2
19
ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
7
(4.01 g,
81%) as a colourless liquid; Rf¼0.40 (heptane/EtOAc, 9:1); 1H NMR
4.1.5. (E)-tert-Butyl 2-[4-(2-ethoxyvinyl)pyridin-3-yl]pyrrolidine-1-
carboxylate (10). In an MW vial were successively added SPhos
(30 mg, 7 mol %), Pd(OAc)2 (8 mg, 3.5 mol %), K3PO4 (450 mg,
(300 MHz):
d
7.03 (d, J¼14.6, 1H), 4.43 (d, J¼14.6, 1H), 3.84 (q, J¼6.9,
2H),1.30 (t, J¼6.9, 3H),1.26 (s,12H); 13C NMR (75 MHz):
d 163.1, 87.6
(br s), 82.8 (2C), 64.5, 25.0 (4C), 14.8.
2.12 mmol, 2 equiv), 4-chloropyridine 9 (300 mg, 1.06 mmol,
1 equiv), boronic ester 7 (399 mg, 2.02 mmol, 1.9 equiv), CH3CN
(3 mL) and water (2 mL). The MW vial was purged with N2 for
5 min then heated at 85 ꢁC for 3 h under MW conditions. The
resulting mixture was filtered through a pad of CeliteÒ and the pad
was washed several times with EtOAc. The filtrate was washed with
brine, dried over Na2SO4, filtered and concentrated in vacuo. The
crude material was purified by column chromatography using
EtOAc as eluent to provide (E)-tert-butyl 2-[4-(2-ethoxyvinyl)pyr-
idin-3-yl]pyrrolidine-1-carboxylate 10 (240 mg, 71%) as an orange
4.1.3. tert-Butyl 4-(4-chloropyridin-3-yl)-4-oxobutylcarbamate (8). To
a solution of diisopropylamine (266 L, 1.90 mmol, 2.5 equiv) in dry
m
THF (2 mL) under N2 at ꢀ78 ꢁC was added n-BuLi (1.3 M in hexanes,
1.46 mL,1.90 mmol, 2.5 equiv). The resulting pale yellow solution was
stirred at this temperature for 10 min then warmed up to 0 ꢁC, stirred
at this temperature for 10 min then cooled back to ꢀ78 ꢁC and
transferred via cannula to a suspension of 4-chloropyridine hydro-
chloride 5 (114 mg, 0.76 mmol,1 equiv) in dry THF (1 mL) over 5 min.

1420
F. Crestey et al. / Tetrahedron 68 (2012) 1417e1421
oil; the product was identified as a mixture of 2 rotamers in a 1.2:1
1H), 4.07 (q, J¼7.2, 0.8H), 3.98 (q, J¼7.2,1.2H), 3.17e3.27 (m, 2H), 2.93e3.01
(m, 2H), 1.87e2.02 (m, 2H), 1.34e1.46 (m, 12H); 13C NMR (75 MHz):
ratio; Rf¼0.40 (EtOAc); 1H NMR (300 MHz):
d 8.17e8.34 (m, 2H),
7.11 (d, J¼5.3, 1H), 6.99 (d, J¼12.4, 1H), 5.89 (d, J¼12.4, 1H), 5.14 (br
d, J¼7.4, 0.45H), 4.89e5.00 (m, 0.55H), 3.86e4.02 (m, 2H),
3.43e3.72 (m, 2H), 2.12e2.37 (m, 1H), 1.67e1.98 (m, 3H), 1.45 (s,
d 202.4, 156.1, 153.4, 151.3, 150.1, 144.5, 130.7, 119.3, 101.8, 79.3, 66.1, 40.1,
39.3, 28.6 (3C), 24.8, 14.9; HRMS (EI): MHþ found 335.1967. C18H26N2O4
requires 335.1971.
4H), 1.29e1.40 (3H), 1.18 (s, 5H); 13C NMR (75 MHz):
d 154.4*, 154.3,
151.64*, 151.59, 148.1*, 147.9, 147.4, 146.5*, 141.6*, 141.3, 135.6,
134.4*, 119.0*, 118.8, 101.0, 80.0*, 79.8, 66.7, 66.4*, 57.3, 56.9*, 47.6*,
47.4, 34.6, 33.2*, 28.9 (3C)*, 28.5 (3C), 23.5, 15.2; *signal corre-
sponding to the minor rotamer; HRMS (EI): MHþ found 319.2036.
C18H26N2O3 requires 319.2022.
4.1.8. 5,6,8,9,10,10a-Hexahydropyrrolo[2,1-a][2,7]naphthyridine (4)
from compound 11. To a solution of pyridine 11 (335 mg, 1.00 mmol,
1 equiv) in CH2Cl2 (3 mL) was added dropwise TFA (3 mL) at 0 ꢁC.
The reaction was allowed to warm up to room temperature and
stirred at this temperature for 3 h. After removing solvents in vacuo
the resulting material was dissolved in MeOH (6 mL) and cooled to
0 ꢁC prior to the portionwise addition of NaBH4 (189 mg,
5.00 mmol, 5 equiv). The reaction was allowed to warm up to room
temperature and stirred at this temperature for 2 h then quenched
by addition of an aqueous solution of HCl (1 M, 3 mL). The reaction
mixture was basified by addition of a saturated aqueous solution of
K2CO3 and extracted with CH2Cl2 (5ꢂ15 mL). The combined organic
layers were washed with brine, dried over Na2SO4, filtered and
concentrated in vacuo. The crude material was purified by column
chromatography using EtOAc/MeOH/TEA (30:2:1) as eluent to fur-
4.1.6. 5,6,8,9,10,10a-Hexahydropyrrolo[2,1-a][2,7]naphthyridine (4)
from compound 10. To
a solution of pyridine 10 (140 mg,
0.44 mmol, 1 equiv) in CH2Cl2 (1 mL) was added dropwise TFA
(1 mL) at 0 ꢁC. The reaction was allowed to warm up to room
temperature and stirred at this temperature for 3 h. After removing
solvents in vacuo the resulting material was dissolved in MeOH
(4 mL) and cooled to 0 ꢁC prior to the portionwise addition of
NaBH4 (83 mg, 2.20 mmol, 5 equiv). The reaction was allowed to
warm up to room temperature and stirred at this temperature for
2 h then quenched by addition of an aqueous solution of HCl (1 M,
2 mL). The reaction mixture was basified by addition of a saturated
aqueous solution of K2CO3 and extracted with CH2Cl2 (5ꢂ10 mL).
The combined organic layers were washed with brine, dried over
Na2SO4, filtered and concentrated in vacuo. The crude material was
purified by column chromatography using EtOAc/MeOH/TEA
(30:2:1) as eluent to furnish 5,6,8,9,10,10a-hexahydropyrrolo[2,1-a]
[2,7]naphthyridine 4 (61 mg, 80%) as a pale yellow oil; Rf¼0.20
nish 5,6,8,9,10,10a-hexahydropyrrolo[2,1-a][2,7]naphthyridine
4
(74 mg, 43%) as a pale yellow oil.
4.1.9. (E)-tert-Butyl 4-[3-(2-ethoxyvinyl)pyridin-4-yl]-4-oxobutylcar-
bamate (13). To a solution of diisopropylamine (168 mL, 1.20 mmol,
1.2 equiv) in dry THF (2 mL) under N2 at ꢀ78 ꢁC was added n-BuLi
(2.5 M in hexanes, 480 mL, 1.20 mmol, 1.2 equiv). The resulting pale
yellow mixture was stirred at this temperature for 10 min then
warmed up to 0 ꢁC and stirred at this temperature for 10 min. After
cooling back to ꢀ78 ꢁC, a solution of 3-chloropyridine 12 (113 mg,
1.00 mmol, 1 equiv) in dry THF (2 mL) was added dropwise and the
reaction was stirred at ꢀ78 ꢁC for 1 h. After addition of a solution of
pyrrolidinone 6 (241 mg, 1.30 mmol, 1.3 equiv) in dry THF (3 mL)
over 2 min, the resulting reaction mixture was stirred at ꢀ78 ꢁC for
2 h then allowed to slowly warm up to room temperature and
stirred at this temperature for 30 min. The resulting solution was
quenched with water and extracted with CH2Cl2 (4ꢂ20 mL) then the
combined organic layers were washed with brine, dried over
Na2SO4, filtered and concentrated in vacuo. The crude material was
dissolved in CH3CN (3 mL) and added into an MW vial containing
SPhos (25 mg, 6 mol %), Pd(OAc)2 (7 mg, 3 mol %), K3PO4 (425 mg,
2.00 mmol, 2 equiv), boronic ester 7 (376 mg, 1.90 mmol, 1.9 equiv)
and water (2 mL). The MW vial was purged with N2 for 5 min then
heated at 85 ꢁC for 2 h under MW conditions. The resulting mixture
was filtered through a pad of CeliteÒ and the pad was washed sev-
eral times with EtOAc. The filtrate was washed with brine, dried over
Na2SO4, filtered and concentrated in vacuo. The crude material was
purified by column chromatography using Et2O/PE (20:1) as eluent
(EtOAc/MeOH/TEA, 30:2:1); 1H NMR (300 MHz):
1H), 8.29 (s, 1H), 7.02 (d, J¼5.0, 1H), 3.38 (br t, J¼8.5, 1H), 3.18e3.26
(m, 1H), 3.01e3.15 (m, 2H), 2.82 (br dt, J¼17.3, 3.6, 1H), 2.36e2.69
(m, 3H), 1.84e2.05 (m, 2H), 1.68e1.82 (m, 1H); 13C NMR (75 MHz):
d
8.31 (d, J¼5.0,
d
147.28, 147.27, 143.6, 135.0, 123.5, 61.7, 53.4, 48.2, 29.9, 28.5, 22.5;
HRMS (EI): MHþ found 175.1231. C11H14N2 175.1235.
4.1.7. (E)-tert-Butyl 4-[4-(2-ethoxyvinyl)pyridin-3-yl]-4-oxobutylcarbamate
(11). To a solution of diisopropylamine (701 mL, 5.00 mmol, 2.5 equiv) in
dry THF (5 mL) under N2 at ꢀ78 ꢁC was added n-BuLi (1.3 M in hexanes,
3.8 mL, 5.00 mmol, 2.5 equiv). The resulting pale yellow solution was
stirred at this temperature for 10 min then warmed up to 0 ꢁC, stirred at
this temperature for 10 min then cooled back to ꢀ78 ꢁC and transferred
via cannula to a suspension of 4-chloropyridine hydrochloride 5 (300 mg,
2.00 mmol, 1 equiv) in dry THF (3 mL) over 5 min. The orange reaction
mixture was stirred at ꢀ78 ꢁC for 1 h prior to the addition of a solution of
pyrrolidinone 6 (481 mg, 2.60 mmol, 1.3 equiv) in dry THF (4 mL) over
5 min. The resulting reaction mixture was stirred at ꢀ78 ꢁC for 2 h then
allowed to slowly warm up to room temperature overnight. The resulting
solution was quenched with water and extracted with EtOAc (2ꢂ60 mL)
then the combined organic layers were washed with brine, dried over
Na2SO4, filtered and concentrated in vacuo. The crude material was dis-
solved in CH3CN (6 mL) and added into an MW vial containing SPhos
(49 mg, 6 mol %), Pd(OAc)2 (14 mg, 3 mol %), K3PO4 (849 mg, 4.00 mmol,
2 equiv), boronic ester 13 (753 mg, 3.80 mmol, 1.9 equiv) and water
(4 mL). The MW vial was purged with N2 for 5 min then heated at 85 ꢁC
for 70 min under MW conditions. The resulting mixture was filtered
through a pad of CeliteÒ and the pad was washed several times with
EtOAc. The filtrate was washed with brine, dried over Na2SO4, filtered and
concentrated in vacuo. The crude material was purified by column chro-
matography using a gradient elution (Et2O/EtOAc, 10:1 to 10:3) to yield (E)-
tert-butyl 4-[4-(2-ethoxyvinyl)pyridin-3-yl]-4-oxobutylcarbamate 11
(362 mg, 54%) as a yellow oil, which solidified; the product was identified
as a mixture of 2 rotamers in a 1.5:1 ratio; mp 90e93 ꢁC; Rf¼0.25 (Et2O/
to
oxobutylcarbamate 13 (265 mg, 79%) as a yellow oil; Rf¼0.35
(Et2O/PE, 20:1); 1H NMR (300 MHz):
yield
(E)-tert-butyl
4-[3-(2-ethoxyvinyl)pyridin-4-yl]-4-
d
8.63 (s, 1H), 8.43 (d, J¼5.0,
1H), 7.28 (d, J¼5.0, 1H), 6.90 (d, J¼12.9, 1H), 6.12 (d, J¼12.9, 1H), 4.71
(br s, 1H), 3.92 (q, J¼7.2, 2H), 3.10ꢀ3.24 (m, 2H), 2.88 (t, J¼7.2, 2H),
1.87 (quint, J¼7.2, 2H), 1.41 (s, 9H), 1.34 (t, J¼7.2, 3H); 13C NMR
(75 MHz): d 203.8, 156.2, 151.0, 148.3, 147.1, 142.4, 129.8, 121.0, 100.5,
79.6, 66.1, 40.2, 39.5, 28.7 (3C), 24.7, 15.1; HRMS (EI): MHþ found
335.1964. C18H26N2O4 requires 335.1971.
4.1.10. 5,6,8,9,10,10a-Hexahydropyrrolo[2,1-a][2,6]naphthyridine
(14). To a solution of pyridine 13 (285 mg, 0.85 mmol, 1 equiv) in
CH2Cl2 (3 mL) was added dropwise TFA (3 mL) at 0 ꢁC. The reaction
was allowed to warm up to room temperature and stirred at this
temperature for 3 h. After removing solvents in vacuo the resulting
material was dissolved in MeOH (5 mL) and cooled to 0 ꢁC prior to
the portionwise addition of NaBH4 (161 mg, 4.26 mmol, 5 equiv).
EtOAc, 10:1); 1H NMR (300 MHz):
d 8.79 (s, 0.6H), 8.73 (s, 0.4H), 8.51 (d,
J¼5.5, 0.4H), 8.45 (d, J¼5.5, 0.6H), 8.02 (d, J¼5.5, 0.4H), 7.30 (d, J¼5.5, 0.6H),
7.20 (d, J¼12.9, 0.6H), 6.45e6.52 (m, 1H), 5.79 (d, J¼7.2, 0.4H), 4.62 (br s,

F. Crestey et al. / Tetrahedron 68 (2012) 1417e1421
1421
Albuquerque, E. X.; Perpeira, E. F. R.; Alkondon, M.; Rogers, W. R. Physiol. Rev.
2009, 89, 73e120.
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The reaction was allowed to warm up to room temperature and
stirred at this temperature for 2 h then quenched by addition of an
aqueous solution of HCl (1 M, 3 mL). The reaction mixture was
basified by addition of a saturated aqueous solution of K2CO3 and
extracted with CH2Cl2 (5ꢂ15 mL). The combined organic layers
were washed with brine, dried over Na2SO4, filtered and concen-
trated in vacuo. The crude material was purified by column chro-
matography using EtOAc/MeOH/TEA (30:2:1) as eluent to give
5,6,8,9,10,10a-hexahydropyrrolo[2,1-a][2,6]naphthyridine
(74 mg, 50%) as a pale yellow oil; Rf¼0.15 (EtOAc/MeOH/TEA,
30:2:1); 1H NMR (300 MHz):
14
5. (a) Chavdarian, C. G.; Seeman, J. I.; Wooten, J. B. J. Org. Chem. 1983, 48, 492e494;
(b) Xu, R.; Dwoskin, L. P.; Grinevich, V.; Sumithran, S. P.; Crooks, P. A. Drug Dev.
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Dwoski, L. P.; Crooks, P. A. Tetrahedron Lett. 2011, 52, 2667e2669.
6. For recent syntheses of conformationally constrained nicotine analogues, see:
d
8.30 (s, 1H), 8.29 (d, J¼5.0, 1H), 6.93
(d, J¼5.0, 1H), 3.39 (br t, J¼8.5, 1H), 3.15e3.23 (m, 1H), 2.94e3.09
(m, 2H), 2.78 (br dt, J¼16.8, 3.6, 1H), 2.59e2.69 (m, 1H), 2.52 (dt,
J¼8.6 and J¼8.0, 1H), 2.26e2.38 (m, 1H), 1.78e1.99 (m, 2H),
1.61e1.75 (m, 1H); 13C NMR (75 MHz):
d 149.8, 147.6, 147.1, 130.2,
€
(a) Lindstrom, S.; Ripa, L.; Hallberg, A. Org. Lett. 2000, 2, 2291e2293; (b) Sarkar,
120.6, 62.6, 53.2, 48.0, 29.9, 25.7, 22.5; HRMS (EI): MHþ found
175.1226. C11H14N2 requires 175.1235.
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Acknowledgements
The authors thank the Danish Council for Independent
ResearchdMedical Sciences for financial support.
8. Whelligan, D. K.; Thomson, D. W.; Taylor, D.; Hoelder, S. J. Org. Chem. 2010, 75,
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9. Jensen, T.; Pedersen, H.; Bang-Andersen, B.; Madsen, R.; Jørgensen, M. Angew.
Supplementary data
Chem., Int. Ed. 2008, 47, 888e890.
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therein.
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Copies of 1H and 13C NMR spectra for compounds 4, 11, 13 and
14. Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2011.12.029.
References and notes
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13. 3,4-Disubstituted pyridines 10 and 11 were also identified as a mixture of 2
rotamers. See Experimental section for more details.
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