Synthesis of conformationally restricted nicotine analogues by intramolecular [3+2] cycloaddition

Article abstract of DOI:10.1016/j.tet.2005.12.032

We describe the synthesis of a series of conformationally constrained nicotine analogues 2-5 from appropriate pyridine-containing enals, featuring an intramolecular azomethine ylide-alkene [3+2] cycloaddition. The objective of the current project is to develop new selective nAChRs-targeting ligands. Of the nicotine analogues that we have studied, the conformation-restricting ring B unit can be either a five-membered carbocycle, or a six-membered carbocycle or heterocycle. The present work constitutes a general method for rapid assembly of other related tricyclic nicotine analogues.

Full text of DOI:10.1016/j.tet.2005.12.032

Tetrahedron 62 (2006) 2240–2246
Synthesis of conformationally restricted nicotine analogues
by intramolecular [3D2] cycloaddition
a,†
Xiaobao Yang, Shengjun Luo, Fang Fang, Peng Liu, Yong Lu,
a,‡
a
a
b
b
Mingyuan He and Hongbin Zhai
*
a
Laboratory of Modern Synthetic Organic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
b
Shanghai Key Laboratory of Green Chemistry and Chemical Processes (GCCP), Department of Chemistry,
East China Normal University, Shanghai 200062, China
Received 28 October 2005; revised 5 December 2005; accepted 6 December 2005
Available online 9 January 2006
Abstract—We describe the synthesis of a series of conformationally constrained nicotine analogues 2–5 from appropriate pyridine-
containing enals, featuring an intramolecular azomethine ylide–alkene [3C2] cycloaddition. The objective of the current project is to
develop new selective nAChRs-targeting ligands. Of the nicotine analogues that we have studied, the conformation-restricting ring B unit can
be either a five-membered carbocycle, or a six-membered carbocycle or heterocycle. The present work constitutes a general method for rapid
assembly of other related tricyclic nicotine analogues.
q 2005 Elsevier Ltd. All rights reserved.
1
. Introduction
approaches have illustrated that the two rings of nicotine
structure are skewed and approximately perpendicular
to one another in order to secure low energy
(
K)-Nicotine (1, Fig. 1) is a well-known alkaloid present
3
,6
in tobacco at 0.2–5% levels and can target and activate
nicotinic acetylcholine receptors (nAChRs), a family of
ligand-gated ion channels widely distributed in the human
brain. These receptors participate in various biological
2
processes related to numerous nervous system disorders.
Over the past decades, nicotine analogues have aroused
tremendous attention in the areas of both organic synthesis
and medicinal chemistry, because of the therapeutic
potential of (K)-nicotine for the central nervous system
conformations.
Aiming at the cures for nervous system disorders, we have
been engaged in designing, synthesizing, and evaluating
new selective nAChRs-targeting ligands for years. In this
paper, we wish to disclose our findings in constructing
conformationally restricted, tricyclic, nicotine analogues
1
4
a,b 4j 4g,7
2,
was achieved as a result of a one- (in 2) or two-atom (in 3–5)
3, 4,
and 5 (Fig. 1). The conformational rigidity
0
(
CNS) disorders such as Alzheimer’s, Parkinson’s, and
bridge erected between C-4 and C-5 of nicotine (1). Our
synthesis features an intramolecular azomethine ylide–
alkene [3C2] cycloaddition
the tricyclic framework of these ligands.
2
Tourette’s diseases. Among the nicotine analogues, those
with constrained conformation have emerged as the most
attractive candidates for new selective nAChRs-targeting
4
a,b,8
in effectively assembling
2
a,3,4
ligands.
This phenomenon might partially be
accounted for by the discovery of epibatidine, an alkaloid
with a rigid structure, which displays strong activity
5
despite of its toxicity. Furthermore, molecular modeling
H
H
H
5
'
X
N
4
N
Keywords: Conformationally restricted; Intramolecular [3C2] cyclo-
addition; Nicotine analogues; Synthesis.
Me
N
N
H
Me
*
Corresponding author. Tel.: C86 21 54925163; fax: C86 21 64166128;
e-mail: zhaih@mail.sioc.ac.cn
Me
N
N
1
2
3: X = CH
†
2
Current address: Graduate School, East China University of Science and
Technology, 130 Meilong Road, Shanghai, China 200237.
Current address: Unilever Research China, 3/F, Xinmao Building, 99
Tianzhou Road, Shanghai, China 200233.
Conformation
4
: X = O
constrainers circled
5: X = S
‡
Figure 1.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.12.032

X. Yang et al. / Tetrahedron 62 (2006) 2240–2246
2241
2
. Results and discussion
yield, setting the stage for intramolecular azomethine ylide–
alkene [3C2] cycloaddition. After extensive experimen-
tation, we found that treatment of 12 with sarcosine in DMF
at 100–110 8C for 6 h effected the desired cycloaddition to
give two isomers 13a/13b in a combined yield of 84% and
The general strategy to synthesize the nicotine analogues in
question is outlined in Figure 2. The ligands represented by
structure 6 were envisioned to be obtainable from
appropriate pyridine-containing enal 8 via azomethine
ylide 7. Intramolecular [3C2] cycloaddition constitutes a
perfect choice in achieving the desired transformation.
1
in a diastereomeric ratio of 1.37:1 (deduced from H NMR
integrals). The structures of 13a and 13b were assigned
based on the coupling constants for the hydrogen atoms at
C-4 (JZ8.1, 4.5 Hz, respectively). Deprotection of 13a/13b
mixture (4 M HCl, 50–60 8C) followed by zinc-mediated
reductive dehydroxylation (Zn powder, formic acid, reflux)
H
R
C
R
R
4
b
B
N
N+
afforded 2 in 84% overall yield for the two steps.
CHO
Me
Me
H
A
A second-generation synthesis of 2 was accomplished in
only two steps. In this case, the precursor for the
intramolecular azomethine ylide–alkene [3C2] cyclo-
addition, that is, 4-allyl-3-pyridinecarboxaldehyde (15),
was formed efficaciously in a single step from 3-pyridine-
carboxaldehyde (14) via sequential in situ protection, ortho
lithiation, cuprate formation, allylation, and deprotection.
The cuprate formation plays a vital role in minimizing/
N
N
N
8
6
7
Figure 2.
2.1. Synthesis of nicotine analogue with five-membered
carbocyclic ring B
As outlined in Scheme 1, the synthesis of nicotine analogue
commenced from 3-bromopyridine (9). Ortho lithiation
4a
eliminating the extent of multiple alkylation.
2
with LDA at K90 8C followed by treatment with acrolein at
the same temperature furnished alcohol 10 in good yield
2.2. Synthesis of nicotine analogue with six-membered
carbocyclic ring B
(
75%). Deprotonation at lower temperature than K78 8C
resulted in higher yield of the product by diminishing
pyridyne formation. Alcohol 10 was protected as ether 11
by exposure to MOMCl in the presence of NaH. Use of a
slight excess of base, compared to MOMCl, was found to be
effective in preventing the formation of the rearranged
enol ether byproducts. Formylation of 11 (BuLi, K78 8C;
DMF, K78 8C) led conveniently to aldehyde 12 in 92%
As shown in Scheme 2, the synthesis of 3 started with a
known alcohol, 16, which was prepared by a Barbier
reaction of 3-bromo-4-pyridinecarboxaldehyde with allyl
9
bromide and zinc powder. Protection of 16 as MOM ether
(
(
NaH, rt; MOMCl, rt, 98%) followed by formylation at C-3
BuLi, K78 8C; DMF, K78 8C, 94%) afforded enal 18 in
high yield. Exposure of 18 to sarcosine in DMF at 120–
30 8C for 8 h effected the desired intramolecular
1
HO
azomethine ylide–alkene [3C2] cycloaddition to produce
a pair of diastereomers 19 (drZ2.57:1) in a combined yield
of 84%. By following the protocol developed for 13a/13b
o
o
LDA, –90 C;
NaH, 10–20 C;
Br
o
Br
acrolein, –90 C
MOMCl, rt
(Scheme 1), the cycloaddition products 19 underwent
deprotection (6 M HCl, 50–60 8C) and the subsequent
zinc-mediated reductive dehydroxylation (Zn powder,
75%
92%
N
9
N
10
o
MOMO
MOMO
BuLi, –78 C;
sarcosine
o
HO
MOMO
o
o
BuLi, –78 C;
o
DMF, –78 C
100–110 C
NaH;
MOMCl
Br
CHO
Br
Br
DMF, –78 C
9
2%
84%
3a/13b = 1.37:1
1
98%
94%
N
N
N
N
17
1
1
12
1
6
R2
H
H
H
H
R1
MOMO
MOMO
H
sarcosine
MOMO
o
N
N
120–130 C
N
CHO
Me
H
Me
8
4%
Me
N
N
N
N
1
1
2
1
1
3a: R = OMOM, R = H
3b: R = H, R = OMOM
2
18
H
H
H
MOMO
o
o
a) HCl, 50–60 C
a) HCl, 50–60 C
b) Zn, HCO H, reflux
N
b) Zn, HCO H, reflux
2
2
N
N
H
Me
H
H
84% (two steps)
Me
93% (two steps)
Me
N
N
N
2
19
3
Scheme 1.
Scheme 2.

2242
X. Yang et al. / Tetrahedron 62 (2006) 2240–2246
4
formic acid, reflux) to lead to 3 in 93% overall yield for the
two steps.
j
Cl
S
N
allyl mercaptan
NaOH, 0 C
CHO
o
CHO
7
6%
2.3. Synthesis of nicotine analogue with six-membered
oxygen-containing heterocyclic ring B
N
20
24
H
The preparation of the cycloaddition precursor, enal 23, was
not as trivial as expected. Direct treatment of 4-chloro-3-
pyridinecarboxaldehyde (20) with allyl alcohol and KOH
in refluxing THF gave rise to 4-chloro-3-(hydroxymethyl)-
pyridine. However, after being protected as the acetal 21
sarcosine
S
N
o
125–130 C
1
0
N
H
91%
Me
5
(
ethylene glycol, TsOH$H O, benzene, reflux, 87%), the
2
etherification at the C-4 of the pyridine ring (allyl alcohol,
KOH, THF, reflux) proceeded cleanly to furnish allyl ether
Scheme 4.
3. Conclusion
2
2 in 92% (Scheme 3). Heating 22 with oxalic acid
dihydrate in refluxing acetone–water (1/1) effected acetal
deprotection to provide in 87% yield enal 23, which
underwent intramolecular azomethine ylide–alkene [3C2]
cycloaddition to form the oxygen-containing tricycle 4 in
moderate yield (72%) when heated with sarcosine in DMF
at 100–110 8C.
In summary, we have accomplished the synthesis of a
series of conformationally constrained nicotine analogues
2
–5 from appropriate pyridine-containing enals, featuring
an intramolecular azomethine ylide–alkene [3C2] cyclo-
addition. The objective of the current project is to develop
new selective nAChRs-targeting ligands. Of the nicotine
analogues that we have studied, the conformation-
restricting ring B unit can be either a five-membered
carbocycle, or a six-membered carbocycle or heterocycle.
The pharmacological investigations of these compounds
are under way. The present work constitutes a general
method for rapid assembly of other related tricyclic
nicotine analogues.
Cl
Cl
N
O
(
CH OH)
TsOH,
2
2
CHO
O
8
7%
N
2
0
21
allyl alcohol
KOH,
O
N
O
H2C2O4,
87%
O
4. Experimental
92%
22
4
.1. General
H
Melting points are uncorrected. NMR spectra were recorded
in CDCl ( H at 300 MHz and C at 75.47 MHz) using
O
sarcosine
100–110 C
O
1
13
o
3
CHO
N
TMS as the internal standard. Column chromatography was
performed on silica gel. CH Cl , DMF and diisopropyl-
H
72%
Me
2
2
N
N
amine were stored over calcium hydride and freshly distilled
prior to use. THF and benzene were distilled over sodium
benzophenone ketyl prior to use. Ethanol was distilled over
magnesium prior to use.
2
3
4
Scheme 3.
2.4. Synthesis of nicotine analogue with six-membered
sulfur-containing heterocyclic ring B
4
.1.1. 3-Bromo-4-(1-hydroxy-2-propenyl)pyridine (10).
BuLi (1.6 M, 8.00 mL, 12.8 mmol) was added to a solution
of diisopropylamine (2.00 mL, 14.3 mmol) in THF (26 mL)
at K78 8C over 10 min. After 30 min, the resultant LDA
solution was cooled to K90 8C, and a solution of
1
0
Reaction 4-chloro-3-pyridinecarboxaldehyde (20) with
allyl mercaptan (generated in situ from thiourea and allyl
bromide in basic medium) and NaOH in ethanol at rt
resulted in the formation of thioether 24 (76%) (Scheme 4),
which was contrary to what we observed with the
etherification of 20 with allyl alcohol. Obviously the
reaction condition for thioetherification was much milder
because of the stronger nucleophilicity of allyl mercaptan
compared to that of allyl alcohol. Finally, upon treatment
with sarcosine in hot DMF (125–130 8C), enal 24 was
converted to the sulfur-containing tricycle 5 in 91% yield
through intramolecular azomethine ylide–alkene [3C2]
cycloaddition. According to our literature search, compound
3
-bromopyridine (0.90 mL, 9.3 mmol) in THF (3 mL) was
added dropwise at this temperature over 3 min. The mixture
was stirred for 25 min, and then a solution of acrolein
(1.10 mL, 16.5 mmol) in THF (5 mL) was added dropwise
over 40 min. The mixture was warmed up to K78 8C and
stirred for 2 h, quenched with saturated aqueous NaHCO3
solution (2 mL) at K78 8C, warmed up to rt, and
evaporated. The residue was partitioned between CH Cl
and aqueous NaHCO solution. The aqueous layer was
3
extracted with CH Cl and the combined organic layers
2
were washed with brine, dried over MgSO , filtered, and
4
2
2
2
5 represents a new nicotine analogue with restricted
conformation.
concentrated. The residue was chromatographed (EtOAc/
hexanes, 1:10–1:5) to give 10 (1.50 g, 75%) as colorless

X. Yang et al. / Tetrahedron 62 (2006) 2240–2246
2243
1
1
crystals: mp 61–62 8C; H NMR (CDCl , 300 MHz) d 4.07–
.21 (br s, 1H), 5.22 (d, JZ0.9 Hz, 1H), 5.25–5.50 (m, 2H),
mixture (1.15 g, 84%, 13a/13bZ1.37:1, as judged by H
NMR integrals of 13a/13b mixture) as a pale yellow oil,
which was suitable for use in the next step. Compound 13a:
3
4
5
4
7
.88–5.99 (m, 1H), 7.52 (d, JZ4.8 Hz, 1H), 8.40 (d, JZ
1
.8 Hz, 1H), 8.54 (s, 1H); C NMR (CDCl , 75 MHz) d
3
1
R Z0.23; H NMR (CDCl , 300 MHz) d 1.86–1.89 (m, 1H),
f
3
3
2.3, 116.9, 120.4, 122.5, 137.0, 148.3, 151.1, 151.4. MS
(EI): 215, 213 (M ). Anal. Calcd for C H BrNO: C, 44.89;
8 8
H, 3.77; N, 6.54. Found: C, 45.02; H, 3.57; N, 6.40.
1.98–2.00 (m, 1H), 2.58–2.62 (m, 1H), 2.63 (s, 3H), 2.86–
2.92 (m, 1H), 3.28–3.33 (m, 1H), 3.50 (s, 3H), 3.98 (d, JZ
7.8 Hz, 1H), 4.82–4.83 (m, 2H), 5.04 (d, JZ8.1 Hz, 1H),
C
1
3
7.29–7.33 (m, 1H), 8.52–8.55 (m, 1H), 8.67 (s, 1H);
C
4
.1.2. 3-Bromo-4-(1-(methoxymethoxy)-2-propenyl)-
NMR (CDCl , 75 MHz) d 24.2, 41.8, 46.0, 55.8, 57.2, 71.6,
3
pyridine (11). To a 100-mL three-necked flask equipped
with two dropping funnels and a nitrogen gas inlet tube,
were added 60% mineral oil dispersion of NaH (620 mg,
77.9, 96.4, 120.3, 138.1, 147.0, 148.8, 151.4. MS (EI): 235
C
(M CH). Anal. Calcd for C13
N, 11.96. Found: C, 66.39; H, 7.87; N, 11.89. Compound
H N O : C, 66.64; H, 7.74;
18 2 2
1
1
5.5 mmol) and anhydrous THF (50 mL). While the
temperature of the suspension was maintained between
0–20 8C, a solution of 10 (2.20 g, 10.3 mmol) in THF
10 mL) was added dropwise over 10 min. Then a solution
13b: R Z0.20; H NMR (CDCl , 300 MHz) d 1.88–1.96 (m,
f 3
1H), 2.23–2.27 (m, 1H), 2.50 (s, 3H), 2.52–2.58 (m, 1H),
3.03–3.11 (m, 2H), 3.46 (s, 3H), 3.87 (d, JZ7.8 Hz, 1H),
4.81–4.87 (m, 2H), 5.07 (d, JZ4.5 Hz, 1H), 7.33 (d, JZ
1
(
1
3
of MOMCl (1.02 mL, 13.4 mmol) in THF (15 mL) was
added immediately over 10 min at 10–20 8C. The resultant
mixture was stirred at rt for 3 h. Saturated aqueous NaHCO3
4.8 Hz, 1H), 8.57 (d, JZ4.8 Hz, 1H), 8.64 (s, 1H); C NMR
(CDCl , 75 MHz) d 24.1, 41.7, 45.8, 55.7, 57.1, 71.4, 77.8,
96.3, 120.2, 138.0, 146.8, 148.6, 151.3. MS (EI): 234 (M ).
Anal. Calcd for C13 : C, 66.64; H, 7.74; N, 11.96.
3
C
(
20 mL) was added carefully to the solution, and the mixture
H N O
18 2 2
was concentrated to remove THF. The aqueous layer was
extracted with CH Cl and the combined organic layers
were washed with brine, dried over MgSO , filtered, and
Found: C, 66.41; H, 7.80; N, 12.01.
2
2
4
4.1.5. cis-1-Methyl-1,2,3,3a,4,8b-hexahydropyrrolo[3,2-f]-
pyrindine (2). MOM ethers 13a/13b (270 mg, 1.15 mmol)
was heated in 4 M HCl (4 mL) at 50–60 8C for 6 h, cooled to
rt, neutralized with 50% NaOH, and extracted with CHCl3–
IPA (3/1). The combined organic layers were dried
concentrated. The residue was chromatographed (Et O/
2
petroleum ether, 10:1) to give 11 (2.44 g, 92%) as a pale
yellow oil: H NMR (CDCl , 300 MHz) d 3.28 (s, 3H), 4.55
1
3
(
(
(
d, JZ6.7 Hz, 1H), 4.70 (d, JZ6.7 Hz, 1H), 5.20–5.37
m, 3H), 5.70–5.78 (m, 1H), 7.40 (d, JZ5.0 Hz, 1H), 8.45
d, JZ5.0 Hz, 1H), 8.61 (s, 1H); C NMR (CDCl3,
(MgSO ), filtered, and evaporated. The residue was mixed
4
1
3
with zinc powder (560 mg, 8.57 mmol) and formic acid
(12.5 mL), refluxed for 25 h, and cooled to rt. The solid was
filtered off and washed thoroughly with CHCl –IPA (3/1).
7
1
5 MHz) d 55.6, 75.8, 94.2, 118.1, 120.7, 122.6, 134.8,
48.4, 148.7, 151.8. MS (EI): 259, 257 (M ). Anal. Calcd
C
3
for C H BrNO : C, 46.53; H, 4.69; N, 5.43. Found: C,
1
The filtrate was concentrated under reduced pressure, the
residue was diluted with saturated aqueous NaHCO3
solution and extracted with CHCl –IPA (3/1). The
0
12
2
4
6.72; H, 4.80; N, 5.60.
3
4
.1.3. 4-(1-(Methoxymethoxy)-2-propenyl)-3-pyridine-
combined organic layers were dried (MgSO
centrated. The residue was chromatographed (petroleum
ether/CH Cl /MeOH, 10:10:1) to give 169 mg (84%) of 2 as
a pale yellow oil: H NMR (CDCl
4
) and con-
carboxaldehyde (12). BuLi (1.6 M, 2.00 mL, 3.20 mmol)
was added dropwise to a solution of 11 (686 mg,
2
2
1
2
.66 mmol) in THF (25 mL) at K78 8C over 10 min.
After 1 h, a solution of DMF (0.30 mL, 3.9 mmol) in THF
3 mL) was added at K78 8C over 10 min. The mixture was
, 300 MHz) d 1.62–1.74
3
(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, JZ
7.6 Hz, 1H), 7.13 (d, JZ5.2 Hz, 1H), 8.42 (d, JZ5.2 Hz,
(
stirred at this temperature for 1 h, quenched with saturated
aqueous NaHCO solution at K78 8C, warmed up to rt, and
evaporated. The aqueous layer was extracted with CH Cl
2
and the combined organic layers were washed with brine,
dried over MgSO , filtered, and concentrated. The residue
1
3
1H), 8.60 (s, 1H); C NMR (CDCl
40.5, 41.9, 57.6, 73.4, 120.3, 139.2, 145.8, 148.3, 153.0. MS
, 75 MHz) d 32.2, 39.2,
3
3
2
C
(EI): 174 (M ). Anal. Calcd for C11H N : C, 75.82; H,
14 2
8.10; N, 16.08. Found: C, 75.69; H, 7.84; N, 16.38.
4
was chromatographed (EtOAc/petroleum ether, 1:10–1:5)
to afford 12 as a pale yellow oil (506 mg, 92%): H NMR
1
4.1.6. 3-Bromo-4-(1-(methoxymethoxy)-3-butenyl)pyri-
dine (17). To a suspension of NaH (60% in mineral oil,
620 mg, 15.5 mmol) in dry THF (100 mL) under a nitrogen
atmosphere, was added a solution of 16 (2.30 g, 10.1 mmol)
in dry THF (20 mL). After the mixture was stirred at rt for
(
CDCl , 300 MHz) d 3.34 (s, 3H), 4.63 (d, JZ6.6 Hz, 1H),
3
4
.79 (d, JZ6.6 Hz, 1H), 5.22–5.42 (m, 2H), 5.86–5.98 (m,
2
(
H), 7.64 (d, JZ5.2 Hz, 1H), 8.80 (d, JZ5.2 Hz, 1H), 9.01
s, 1H), 10.31 (s, 1H). MS (EI): 207 (M ).
C
20 min, a solution of MOMCl (1.0 mL, 13 mmol) in dry
THF (15 mL) was slowly added. The mixture was stirred at
rt for 2 h, diluted with saturated aqueous NaHCO solution,
3
4
1
.1.4. (3aR,4R*,8bS)-4-(Methoxymethoxy)-1-methyl-
,2,3,3a,4,8b-hexahydropyrrolo[3,2-f]pyrindine (13a)
and (3aS,4R*,8bR)-4-(methoxymethoxy)-1-methyl-
,2,3,3a,4,8b-hexahydropyrrolo[3,2-f]pyrindine (13b). A
mixture of aldehyde 12 (1.21 g, 5.84 mmol) and sarcosine
546 mg, 6.13 mmol) in DMF (30 mL) was heated under N2
at 100–110 8C for 6 h, cooled to rt, and evaporated. The
residue was diluted with brine (10 mL) and extracted with
evaporated, and extracted with CH Cl . The combined
2
2
1
organic layers were washed with brine, dried (MgSO4),
filtered, and concentrated. The residue was chromato-
graphed (EtOAc/petroleum ether, 1:10) to give 17 (2.69 g,
(
1
98%) as a colorless solid: H NMR (CDCl , 300 MHz) d
3
2.43–2.54 (m, 2H), 3.35 (s, 3H), 4.52 (d, JZ6.6 Hz, 1H),
4.63 (d, JZ6.9 Hz, 1H), 5.01 (dd, JZ7.8, 4.4 Hz, 1H), 5.07
(t, JZ1.1 Hz, 1H), 5.11 (d, JZ4.8 Hz, 1H), 5.75–5.90 (m,
1H), 7.42 (d, JZ4.8 Hz, 1H), 8.51 (d, JZ5.1 Hz, 1H), 8.66
CHCl –IPA (3/1). The combined organic layers were dried
3
over MgSO , filtered, and concentrated. The residue was
4
chromatographed (EtOH/CH Cl , 1:10) to give 13a/13b
2
2

2244
X. Yang et al. / Tetrahedron 62 (2006) 2240–2246
1
s, 1H); C NMR (CDCl , 75.47 MHz) d 39.9, 55.6, 75.5,
3
1
The minor product. H NMR (CDCl , 300 MHz) d 1.55–
(
3
3
9
4.9, 117.9, 120.5, 122.3, 133.1, 148.2, 149.8, 151.6. MS
1.65 (m, 1H), 1.73–1.86 (m, 1H), 2.10 (ddd, JZ12.8, 4.1,
2.7 Hz, 1H), 2.17–2.29 (m, 2H), 2.29 (s, 3H), 2.72 (t, JZ
7.4 Hz, 1H), 3.11 (td, JZ8.1, 8.0 Hz, 2H), 3.47 (s, 3H), 4.81
(t, JZ3.9 Hz, 1H), 4.83 (dd, JZ6.8, 1.7 Hz, 1H), 4.91 (dd,
JZ6.9, 1.8 Hz, 1H), 7.51 (d, JZ4.8 Hz, 1H), 8.38 (s, 1H),
8.55 (d, JZ5.1 Hz, 1H).
C
(EI) 272 (M , 25), 230 (36). Anal. Calcd for C H BrNO :
11 14 2
C, 48.55; H, 5.19; N, 5.15. Found: C, 48.41; H, 5.17; N,
5
.19.
4
.1.7. 4-(1-(Methoxymethoxy)-3-butenyl)-3-pyridine-
carboxaldehyde (18). A solution of n-BuLi (2.2 M,
.4 mL, 9.7 mmol) in hexane was added dropwise to a
solution of 17 (2.22 g, 8.16 mmol) in dry THF (80 mL) at
K78 8C under a nitrogen atmosphere. After the mixture was
stirred at K78 8C for 20 min, a solution of DMF (0.95 mL,
4
4.1.9. 2,3,3a,4,5,9b-Hexahydro-1-methyl-1H-pyrrolo[3,2,-h]-
soquinoline (3). A mixture of the two isomers of 19
(399 mg, 1.61 mmol) and 6 M HCl (20 mL) was heated at
50–60 8C under N
saturated aqueous NaHCO
CHCl –IPA (3/1). The combined organic layers were dried
over MgSO , and filtered. Evaporation of the volatiles gave
for 8 h, cooled to rt, neutralized with
2
1
2 mmol) in dry THF (10 mL) was introduced. The mixture
3
solution, and extracted with
was stirred at K78 8C for 30 min, allowed to warm to rt,
stirred at rt for 30 min, diluted with saturated aqueous
NaHCO solution, evaporated, and extracted with CH Cl .
3
4
the crude products of diastereomeric 2,3,3a,4,5,9b-hexa-
hydro-5-hydroxy-1-methyl-1H-pyrrolo[3,2,-h]isoquinoline,
which could be used directly for the next reaction.
3
2
2
The combined organic layers were washed with brine, dried
MgSO ), filtered, and concentrated. The residue was
chromatographed (EtOAc/petroleum ether, 1:10) to give
(
4
1
1
3
6
8 (1.70 g, 94%) as a pale yellow oil: H NMR (CDCl ,
3
A mixture of the above-mentioned crude alcohols and zinc
power (816 mg, 12.5 mmol) in anhydrous formic acid
00 MHz) d 2.22–2.34 (m, 2H), 3.13 (s, 3H), 4.35 (dd, JZ
.9, 1.5 Hz, 1H), 4.47 (dd, JZ6.6, 1.2 Hz, 1H), 4.84–4.86
(40 mL) was heated at reflux for 15 h under N
rt, and evaporated. The residue was diluted with saturated
aqueous NaHCO solution and extracted with CHCl –IPA
(3/1). The combined organic layers were dried over MgSO
filtered, and concentrated. The residue was chromato-
graphed (CH OH/EtOAc, 1:20) to give 3 (281 mg, 93%
for two steps from 19) as a colorless oil: H NMR (CDCl
00 MHz) d 1.56–1.62 (m, 1H), 1.69–1.84 (m, 2H), 2.09–
, cooled to
2
(
1
m, 1H), 4.90 (t, JZ1.2 Hz, 1H), 5.41 (dd, JZ7.5, 4.8 Hz,
H), 5.64–5.70 (m, 1H), 7.46 (d, JZ5.1 Hz, 1H), 8.60 (dd,
3
3
1
3
JZ5.0, 1.4 Hz, 1H), 8.81 (s, 1H), 10.08 (s, 1H); C NMR
CDCl , 75.47 MHz) d 41.2, 55.4, 72.9, 95.0, 117.7, 121.2,
,
4
(
3
1
(
27.8, 133.3, 153.0, 153.6, 154.3, 191.4. MS (EI) 180
MK41, 22), 45 (100).
3
1
,
3
3
4
.1.8. 2,3,3a,4,5,9b-Hexahydro-5-(methoxymethoxy)-1-
2.16 (m, 1H), 2.24–2.39 (m, 1H), 2.34 (s, 3H), 2.51–2.62
(m, 2H), 2.78–2.88 (m, 1H), 3.08–3.11 (m, 2H), 7.09 (dd,
JZ4.7, 2.0 Hz, 1H), 8.34 (d, JZ2.7 Hz, 1H), 8.40 (dd, JZ
methyl-1H-pyrrolo[3,2,-h]isoquinoline (19). A solution
of 18 (534 mg, 2.41 mmol) and sarcosine (236 mg,
2.65 mmol) in DMF (15 mL) was heated at 125–130 8C
under N for 8 h, cooled to rt, and evaporated. The residue
1
3
5.0, 2.9 Hz, 1H); C NMR (CDCl , 75.47 MHz) d 26.1,
3
28.9, 29.7, 36.0, 40.3, 55.6, 64.4, 123.4, 132.1, 148.0, 149.4,
150.2. MS (EI) 188 (M , 68), 187 (100). Anal. Calcd for
2
C
was diluted with brine and extracted with CHCl –IPA (3/1).
3
The combined organic layers were dried over MgSO4,
filtered, and concentrated. The residue was chromato-
graphed (CH OH/EtOAc, 1:20) to give a pair of diaster-
C H N $2HCl$1/3H O (the HCl salt of 3): C, 53.94; H,
12 16 2 2
7.04; N, 10.48. Found: C, 54.04; H, 7.22; N, 10.44.
3
1
eomers 19 (505 mg, 84%) as a pale yellow oil: H NMR
(
4.1.10. 4-Chloro-3-(1,3-dioxolan-2-yl)pyridine (21). A
mixture of 20 (270 mg, 1.91 mmol), ethylene glycol
(0.55 mL, 9.9 mmol) and the p-toluenesulfonic acid
monohydrate (328 mg, 1.72 mmol) in benzene (30 mL)
was boiled for 3 h, cooled to rt, made basic with aqueous
sodium hydroxide solution, and extracted with ether. The
CDCl , 300 MHz) diastereomers, 2.57:1, d 1.53–1.66 (m,
3
1H), 1.70–1.82 (m, 0.28H), 1.88 (td, JZ11.9, 11.7 Hz,
0.72H), 2.05–2.22 (m, 2H), 2.26 (s, 0.84H), 2.41 (dt, JZ9.0,
9.0 Hz, 1H), 2.45 (s, 2.16), 2.49–2.56 (m, 0.72H), 2.67–2.70
(
1
(
6
m, 0.28H), 3.04 (t, JZ7.8 Hz, 0.28H), 3.06 (d, JZ6.6 Hz,
H), 3.24 (td, JZ8.1, 3.0 Hz, 0.72H), 3.47 (s, 0.84H), 3.49
s, 2.16H), 4.60 (dd, JZ11.0, 5.3 Hz, 0.72H), 4.79 (d, JZ
.0 Hz, 0.28H), 4.82 (t, JZ6.5 Hz, 0.28H), 4.83 (d,
combined organic layers were dried (MgSO ), filtered,
4
and concentrated. The residue was chromatographed
(EtOAc/petroleum ether, 1:5) to give 21 (307 mg, 87%) as
, 300 MHz) d 4.00–4.13
1
a colorless oil: H NMR (CDCl
JZ6.3 Hz, 0.72H), 4.91 (d, JZ6.0 Hz, 0.28H), 4.94 (d,
JZ6.0 Hz, 0.72H), 7.46 (d, JZ4.8 Hz, 0.72H), 7.49 (d, JZ
3
(m, 2H), 4.14–4.25 (m, 2H), 6.17 (s, 1H), 7.33 (d, JZ
1
3
5
.1 Hz, 0.28H), 8.37 (s, 0.28H), 8.49 (s, 0.72H), 8.50 (d, JZ
5.4 Hz, 1H), 8.50 (d, JZ5.1 Hz, 1H), 8.77 (s, 1H); C NMR
(CDCl , 75.47 MHz) d 65.6, 99.9, 124.6, 131.1, 143.5,
149.3, 151.0. MS (EI) 184 (MK1). Anal. Calcd for
ClNO : C, 51.77; H, 4.34; N, 7.55. Found: C, 51.81;
5
.1 Hz, 0.72H), 8.54 (d, JZ5.1 Hz, 0.28H). MS (EI) 249
MC1, 7), 248 (M , 0.6), 203 (91), 43 (100). Anal. Calcd
3
C
(
for C H N O : C, 67.71; H, 8.12; N, 11.28. Found: C,
C
H
8
1
4 20 2 2
8
2
6
7.77; H, 7.81; N, 11.21.
H, 4.24; N, 7.43.
1
The major product. H NMR (CDCl , 300 MHz) d 1.56–
4.1.11. 4-(Allyloxy)-3-(1,3-dioxolan-2-yl)pyridine (22). A
mixture of 21 (88 mg, 0.47 mmol), allyl alcohol (0.50 mL,
7.4 mmol) and KOH (819 mg, 14.6 mmol) in THF (20 mL)
was heated at reflux for 6 h, cooled to rt, made basic with
aqueous sodium hydroxide solution, and extracted with
ether. The combined organic layers were dried (MgSO4),
filtered, and concentrated. The residue was chromato-
graphed (EtOAc/petroleum ether, 2:5) to give 22 (90 mg,
3
1
2
.67 (m, 1H), 1.82–1.94 (m, 1H), 2.08–2.20 (m, 2H), 2.40–
.59 (m, 2H), 2.46 (s, 3H), 3.11 (d, JZ5.4 Hz, 1H), 3.25 (td,
JZ9.0, 3.0 Hz, 1H), 3.48 (s, 3H), 4.61 (dd, JZ11.0, 5.3 Hz,
1
1
H), 4.81 (dd, JZ6.9, 1.2 Hz, 1H), 4.94 (dd, JZ6.8, 1.4 Hz,
H), 7.47 (d, JZ5.1 Hz, 1H), 8.47–8.53 (m, 2H); C NMR
13
(
6
CDCl , 75.47 MHz) d 29.4, 33.3, 36.4, 40.7, 55.3, 55.5,
2.9, 73.4, 95.3, 120.2, 130.4, 147.4, 148.1, 150.5.
3

X. Yang et al. / Tetrahedron 62 (2006) 2240–2246
2245
1
2%) as a colorless solid: mp 65–67 8C; H NMR (CDCl ,
C
(M ). Anal. Calcd for C H NOS: C, 60.31; H, 5.06; N,
9 9
9
3
3
00 MHz) d 3.99–4.10 (m, 2H), 4.10–4.21 (m, 2H), 4.66 (d,
7.81. Found: C, 60.41; H, 5.28; N, 7.88.
JZ5.4 Hz, 2H), 5.33 (dd, JZ10.5, 1.2 Hz, 1H), 5.43 (dd,
JZ17.7, 1.2 Hz, 1H), 5.99–6.03 (m, 1H), 6.20 (s, 1H), 6.79
4.1.15. 2,3,3a,4,5,9b-Hexahydro-1-methyl-5-thia-1H-
pyrrolo[3,2,-h]isoquinoline (5). A solution of 24
(136 mg, 0.759 mmol) and sarcosine (74 mg, 0.83 mmol)
(
d, JZ5.7 Hz, 1H), 8.47 (d, JZ6.0 Hz, 1H), 8.62 (s, 1H);
C NMR (CDCl , 75.47 MHz) d 65.4, 68.8, 98.8, 107.2,
1
3
3
1
(
18.4, 122.1, 131.8, 148.8, 152.0, 162.8. MS (EI) 206
MK1). Anal. Calcd for C H NO : C, 63.76; H, 6.32; N,
in DMF (15 mL) was heated at 125–130 8C under N for 8 h,
2
cooled to rt, evaporated, diluted with brine, and extracted
with CHCl –IPA (3/1). The combined organic layers were
1
1
13
3
6
.76. Found: C, 63.76; H, 6.31; N, 6.69.
3
dried over MgSO , filtered, and concentrated. The residue
4
4
.1.12. 4-(Allyloxy)nicotinaldehyde (23). A mixture of 22
was chromatographed (EtOAc/petroleum ether, 2:5) to give
,
1
5 (143 mg, 91%) as a colorless oil: H NMR (CDCl
(
4
180 mg, 0.869 mmol) and oxalic acid dihydrate (547 mg,
.34 mmol) in acetone and water (1:1, 40 mL) was heated at
3
300 MHz) d 1.90–1.94 (m, 1H), 2.14–2.17 (m, 1H), 2.31 (s,
3H), 2.31–2.36 (m, 1H), 2.74 (d, JZ9.9 Hz, 2H), 2.92–2.99
(m, 1H), 3.12–3.19 (m, 2H), 7.18 (d, JZ5.1 Hz, 1H), 8.25
reflux overnight, cooled to rt, made basic with aqueous
sodium hydroxide solution, and extracted with ether. The
combined organic layers were dried (MgSO ), filtered, and
1
3
(s, 1H), 8.26 (d, JZ5.4 Hz, 1H); C NMR (CDCl ,
4
3
concentrated. The residue was chromatographed (EtOAc/
petroleum ether, 2:5) to give 23 (123 mg, 87%) as a
75.47 MHz) d 28.8, 32.0, 37.7, 40.1, 54.5, 63.9, 122.9,
129.0, 147.3, 147.5, 151.7. MS (EI) 206 (M ). Anal. Calcd
for C11H N S: C, 64.04; H, 6.84; N, 13.58. Found: C,
14 2
63.74; H, 7.17; N, 13.97.
C
1
colorless oil: H NMR (CDCl , 300 MHz) d 4.70 (d, JZ
3
5
1
1
1
1
.0 Hz, 2H), 5.36 (dd, JZ10.5, 1.2 Hz, 1H), 5.44 (dd, JZ
7.1, 1.2 Hz, 1H), 5.96–6.09 (m, 1H), 6.88 (d, JZ6.0 Hz,
H), 8.57 (dd, JZ6.0, 1.5 Hz, 1H), 8.85 (s, 1H), 10.46 (s,
Acknowledgements
1
3
H); C NMR (CDCl , 75.47 MHz) d 69.2, 108.1, 119.1,
20.5, 130.9, 150.7, 155.8, 165.7, 188.6; MS (EI) 162
3
We thank NSFC (No. 20372073), STCSM (‘Post-Venus’
Program, No. 05QMH1416), GCCP of ECNU, and Ministry
of Human Resources of PRC for financial support.
(
MK1). Anal. Calcd for C H NO : C, 66.25; H, 5.56; N,
9 9 2
8
.58. Found: C, 65.86; H, 5.56; N, 8.40.
4
.1.13. 2,3,3a,4,5,9b-Hexahydro-1-methyl-5-oxa-1H-pyr-
rolo[3,2,-h]isoquinoline (4). A solution of 23 (156 mg,
.956 mmol) and sarcosine (94.0 mg, 1.06 mmol) in DMF
15 mL) was heated at 100–110 8C under N for 8 h, cooled
References and notes
0
(
2
1. (a) Decker, M. W.; Meyer, M. D.; Sullivan, J. P. Expert Opin.
Investig. Drugs 2001, 10, 1819. (b) Nordberg, A. Biol.
Psychiatry 2001, 49, 200. (c) Paterson, D.; Nordberg, A.
Prog. Neurobiol. 2000, 61, 75. (d) Clementi, F.; Fornasari, D.;
Gotti, C. Eur. J. Pharmacol. 2000, 393, 3.
to rt, and evaporated. The residue was diluted with brine and
extracted with CHCl –IPA (3/1). The combined organic
3
layers were dried over MgSO , filtered, and concentrated.
4
The residue was chromatographed (EtOAc/petroleum ether,
1
:5) to give 4 (131 mg, 72%) as a pale oil: H NMR (CDCl ,
00 MHz) d 1.41–1.46 (m, 1H), 2.08–2.13 (m, 1H), 2.30–
.46 (m, 2H), 2.44 (s, 3H), 2.94 (d, JZ5.1 Hz, 1H), 3.13 (td,
2
3
2
2. (a) McDonald, I. A.; Cosford, N.; Vernier, J.-M. Annu. Rep.
Med. Chem. 1995, 30, 41. (b) Decker, M. W.; Aneric, S. P.
Neuronal Nicotinic Recept. 1999, 395.
3
JZ9.0, 2.1 Hz, 1H), 3.92 (dd, JZ11.4, 10.8 Hz, 1H), 4.12
3. Glennon, R. A.; Dukat, M. Med. Chem. Res. 1996, 465.
4. For our previous work, see: (a) Luo, S.; Fang, F.; Zhao, M.;
Zhai, H. Tetrahedron 2004, 60, 5353. (b) Zhai, H.; Liu, P.;
Luo, S.; Fang, F.; Zhao, M. Org. Lett. 2002, 4, 4385. For a part
of H. Rapoport’s work, see: (c) Lennox, J. R.; Turner, S. C.;
Rapoport, H. J. Org. Chem. 2001, 66, 7078. (d) Turner, S. C.;
Zhai, H.; Rapoport, H. J. Org. Chem. 2000, 65, 861. (e) Xu, Y.-z.;
Choi, J.; Calaza, M. I.; Turner, S. C.; Rapoport, H. J. Org.
Chem. 1999, 64, 4069. For representative work from
other labs, see: (f) Meijler, M. M.; Matsushita, M.;
Altobell, L. J., III,; Wirsching, P.; Janda, K. D. J. Am. Chem.
Soc. 2003, 125, 7164. (g) Sarkar, T. K.; Basak, S.; Slanina, Z.;
Chow, T. J. J. Org. Chem. 2003, 68, 4206. (h) Ullrich, T.;
Binder, D.; Pyerin, M. Tetrahedron Lett. 2002, 43, 177.
(i) Kanne, D. B.; Abood, L. G. J. Med. Chem. 1988, 31, 506.
(j) Glassco, W.; Suchocki, J.; George, C.; Martin, B. R.;
May, E. L. J. Med. Chem. 1993, 36, 3381. (k) Chavdarian,
C. G.; Seeman, J. I.; Wooten, J. B. J. Org. Chem. 1983, 48,
492.
(
dd, JZ10.8, 5.4 Hz, 1H), 6.80 (d, JZ5.4 Hz, 1H), 8.30 (d,
C NMR (CDCl3,
5.47 MHz) d 24.5, 34.0, 39.4, 54.5, 60.1, 67.6, 112.3,
13
JZ5.4 Hz, 1H), 8.34 (s, 1H);
7
117.6, 149.8, 152.7, 161.6. MS (EI) 189 (MK1). Anal.
Calcd for C H N O: C, 69.45; H, 7.42; N, 14.73. Found:
C, 69.30; H, 7.42; N, 14.82.
1
1 14 2
4.1.14. 4-(Allylthio)nicotinaldehyde (24). A solution of
allyl bromide (0.24 mL, 2.8 mmol) and thiourea (210 mg,
2
1
.76 mmol) in absolute ethanol (20 mL) was refluxed for
h. After NaOH (220 mg, 5.50 mmol) was added, the
reaction mixture was refluxed for another 1 h and cooled to
8C. After compound 20 (260 mg, 1.84 mmol) was
introduced to the system, the mixture was stirred at 0 8C
0
for 1 h, diluted with cold water, and extracted with ether.
The combined organic layers were dried (MgSO ), filtered,
4
and concentrated. The residue was chromatographed
(
EtOAc/petroleum ether, 1:5) to give 24 (251 mg, 76%) as
1
a colorless oil: H NMR (CDCl , 300 MHz) d 3.68 (dd, JZ
5. Spande, T. F.; Garraffo, H. M.; Edwards, M. W.; Yeh, H. J. C.;
Pannell, L.; Daly, J. W. J. Am. Chem. Soc. 1992, 114, 3475.
6. Elmore, D. E.; Dougherty, D. A. J. Org. Chem. 2000, 65, 742.
7. For the 1-demethylated derivative, see: Vernier, J.-M.;
Holsenback, H.; Cosford, N. D. P.; Whitten, J. P.;
Menzaghi, F.; Reid, R.; Rao, T. S.; Sacaan, A. I.;
3
5
.4, 1.2 Hz, 2H), 5.29 (dd, JZ9.9, 1.2 Hz, 1H), 5.42 (dd,
JZ17.1, 1.2 Hz, 1H), 5.88–5.95 (m, 1H), 7.29 (d, JZ
5
1
1
.4 Hz, 1H), 8.53 (dd, JZ5.7, 1.2 Hz, 1H), 8.85 (s, 1H),
13
0.2 (s, 1H); C NMR (CDCl , 75.47 MHz) d 33.9, 119.5,
19.8, 128.0, 131.0, 152.2, 153.0, 155.0, 190.3. MS (EI) 179
3

2246
X. Yang et al. / Tetrahedron 62 (2006) 2240–2246
Lloyd, G. K.; Suto, C. M.; Chavez-Noriega, L. E.; Washburn,
M. S.; Urrutia, A.; McDonald, I. A. Bioorg. Med. Chem. Lett.
998, 8, 2173.
9. (a) Zhao, J.; Yang, X.; Jia, X.; Luo, S.; Zhai, H. Tetrahedron
2003, 59, 9379. (b) Yang, X.; Zhao, J.; Yang, L.; Jia, X.; Zhai,
H. Chin. J. Chem. 2003, 21, 970. (c) Jones, K.; Fiumana, A.;
Escudero-Hernandez, M. L. Tetrahedron 2000, 56, 397. (d)
Jones, K.; Fiumana, A. Tetrahedron Lett. 1996, 37, 8049.
10. Marsais, F.; Trecourt, F.; Breant, P.; Queguiner, G.
J. Heterocycl. Chem. 1988, 25, 81.
1
8
. (a) Smith, R.; Livinghouse, T. Tetrahedron 1985, 41, 3559. (b)
Bolognesi, M. L.; Andrisano, V.; Bartolini, M.; Minarini, A.;
Rosini, M.; Tumiatti, V.; Melchiorre, C. J. Med. Chem. 2001,
44, 105.