Toward Pyridine-Heterocycle Patterns through Prins and Aza-Prins Cyclisations: Application to a Short Synthesis of (±)-Anabasine

Article abstract of DOI:10.1002/ejoc.201402971

The formation of pyridine-containing bisheterocycles through a Prins-type cyclisation is described. Pyridine-tetrahydropyran and pyridine-piperidine conjugates could be efficiently obtained using various carbaldehydes including dicarbaldehydes, and either homoallylic alcohols or a homoallylic amine. Selective partial or complete hydrogenation led to new bisheterocycle combinations. A two-step sequence involving an aza-Prins cylisation allowed us to prepare the alkaloid anabasine.

Full text of DOI:10.1002/ejoc.201402971

Job/Unit: O42971
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Date: 15-09-14 11:04:16
Pages: 7
FULL PAPER
DOI: 10.1002/ejoc.201402971
Toward Pyridine–Heterocycle Patterns through Prins and Aza-Prins
Cyclisations: Application to a Short Synthesis of (؎)-Anabasine
Olivier Colin,[a] Christine Greck,[a] Damien Prim,[a] and Christine Thomassigny*[a]
Keywords: Nitrogen heterocycles / Oxygen heterocycles / Natural products / Cyclization / Hydrogenation / Prins reaction
The formation of pyridine-containing bisheterocycles
through a Prins-type cyclisation is described. Pyridine–tetra- led to new bisheterocycle combinations. A two-step se-
hydropyran and pyridine–piperidine conjugates could be quence involving an aza-Prins cylisation allowed us to pre-
allylic amine. Selective partial or complete hydrogenation
efficiently obtained using various carbaldehydes including pare the alkaloid anabasine.
dicarbaldehydes, and either homoallylic alcohols or a homo-
Introduction
Molecular architectures based on the combination of a
pyridine ring and a saturated heterocycle such as a piper-
idine or a tetrahydropyran represent challenging targets in
organic synthesis. For the target compounds in this work,
Figure 1. Target molecules.
we focussed on pyridyl–heterocycle conjugates with dif-
ferent substitution positions, as in targets 1, or with an eth-
The Prins cyclisation reaction, where a homoallylic
ylene-based spacer linking the two heterocycles, as in tar- alcohol reacts with an aldehyde under Brønsted- or Lewis-
gets 2 (Figure 1). Such combinations can be found in alka- acid-promoted conditions, has become one of the major
loids[1] and synthetic biologically active molecules.[2] methods for the synthesis of di- and tetrahydropyrans.[5]
Furthermore, such bisheterocyclic molecules have recently The reaction has also been extended to the preparation of
been shown to be efficient ligands in transition-metal-pro- piperidines in an aza-Prins cyclisation, by the use of a
moted transformations.[3] Despite an increasing number of homoallylic amine.[5a,6]
reports dealing with applications of pyridyl–piperidine or
The general mechanism of the Prins cyclisation is well
pyridyl–tetrahydropyran (THP) based compounds, their known, and involves an aldehyde, a homoallylic alcohol,
preparation suffers from a lack of generality. Pyridyl–THP and an acid.[5a] The acid is essential for activation of the
moieties have only been described in patents.[4] A general aldehyde, and, depending on the experimental conditions,
method for the synthesis of both target structures 1 and 2, it can also act as the nucleophile in the reaction. The Prins
containing either a THP (X = O) or a piperidine (X = NH) reaction is usually initiated by complexation of the acid to
ring, and with this saturated six-membered heterocycle as a the carbonyl moiety, followed by reaction of the activated
substituent at any position of the pyridine ring, remained carbonyl with the homoallylic alcohol. The resulting inter-
elusive. Thus, a strategy to achieve this in a short sequence mediate hemiacetal leads to an oxonium ion, whose more
of reaction steps using commercially available starting ma- stable chair conformation would put the pyridyl substituent
terials would be appealing. In this paper, we describe our in a pseudoequatorial position. A 6-endo cyclisation leads
efforts directed towards the preparation of targets 1 and 2, to the carbocationic key intermediate, which may either be
using a general two-step indium- or titanium-promoted trapped by a nucleophile X– to form compound A, or react
Prins-type reaction.
further to give a mixture of two regioisomers B and C
through an elimination process. Selective access to A, B, or
C is expected, depending on the reaction conditions
(Scheme 1).
The Prins reaction most often requires a minimum of
3 equiv. of acid, which is quite important, as the Lewis acids
that are generally used are quite expensive, and can generate
problems of purification and waste. The use of pyridine de-
[a] ILV – UMR CNRS 8180, Université de
Versailles-St-Quentin-en-Yvelines,
45 avenue des Etats-Unis, 78035 Versailles Cedex, France
E-mail: christine.thomassigny@uvsq.fr
www.ilv.uvsq.fr/recherche/Echo/echo.htm
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402971.
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O. Colin, C. Greck, D. Prim, C. Thomassigny
FULL PAPER
to the expected product (i.e., 5) in 23% yield after 15 h in
refluxing dichloromethane. The reaction proved to be
highly solvent dependent; n-hexane and acetonitrile were
not efficient at all, and toluene led to a 57:42 mixture of 4
and 5 (Table 1, entry 2). When the reaction was run in tolu-
ene, product 4 (X = tolyl) was isolated as a mixture of ortho,
para, and meta regioisomers resulting from the trapping of
the electrophilic carbocationic intermediate by the toluene.
The use of a toluene/dichloromethane mixture (3:1) did not
give any improvement in the yield of 5 (Table 1, entry 3).
Finally, we tried carrying out the Prins reaction in an
Ace pressure tube. The use of a constant-volume reaction
vessel would result in an increase in the internal pressure in
the tube. This would hinder the vaporisation of the homo-
allylic alcohol, which could be partly responsible for the
low yields observed. In addition, the lower volume of the
pressure tube might be beneficial to a reaction with a nega-
tive volume of activation like the Prins reaction. In CH2Cl2,
the yield of product 5 increased when the reaction was run
in the Ace pressure tube from 23 to 61% (Table 1, entry 4).
Changing from CH2Cl2 to toluene resulted in the selective
formation of product 4, albeit in a lower yield (Table 1, en-
try 5). Interestingly, 4 (X = tolyl) was obtained as the sole
product and in a fair yield using an Ace pressure tube in
the presence of 2 equiv. of InBr3 (Table 1, entry 6).
The use of titanium tetrachloride allowed us to access
chlorinated derivative 4 in 42% yield (Table 1, entry 7). A
comparison of Table 1, entries 7 and 8 again highlights the
major role played by the solvent in this reaction. Indeed,
the use of a toluene/CH2Cl2 mixture gave both compounds
4 and 5 in a 42:13 ratio. In contrast, when the reaction was
carried out in CH2Cl2 alone, only chlorinated product 4 was
obtained in 27% yield (Table 1, entry 8).
Most of the Prins reactions described in the literature use
a 3:1 acid/aldehyde ratio. In the context of pyridine-derived
substrates, if the first equivalent of acid interacts with the
pyridinic nitrogen atom and a second equivalent promotes
the cyclisation, the use of such a large excess of acid could
be unnecessary. Thus, we went on to study the effect of
varying the acid/aldehyde ratio on the rate of formation of
derivatives 4 (X = tolyl) and 5.
Scheme 1. Mechanism of the Prins cyclisation.
rivatives as substrates could present an additional hurdle
to be overcome, as a result of potential neutralisation or
complexation of the pyridine with the acid required for the
reaction.
Results and Discussion
As part of a program devoted to the preparation of N-
heterocyclic cores, saturated[7] or pyridine-derived,[8] we
were interested first in developing the Prins reaction of 3-
(pyridin-2-yl)propanal (3)[9] with 3-buten-1-ol, leading to
diastereoisomers 4 and/or regioisomers 5. The main chal-
lenge was to use the Prins reaction with pyridine derivatives,
as we found only one example of such a reaction, and it led
to a THP derivative in only 11% yield.[4d] Thus we first set
out to establish reaction conditions that would allow the
preparation of the target compounds by Prins cyclisation,
and we especially focussed our attention to the acid/sub-
strate ratio.
We started by examining the influence of the nature of
the acid, solvent, and pressure for the preparation of each
product. The results of the most relevant experiments are
summarised in Table 1.
Table 1. Study of the Prins reaction of 3 with 3-buten-1-ol.
Entry[a] Acid (equiv.) Solvent
Product(s)
Yield [%][b]
1
2
In(OTf)3 (3) CH2Cl2
In(OTf)3 (3) toluene
5
23
4 (X = tolyl), 5 57, 42
3
In(OTf)3 (3) toluene/CH2Cl2 (3:1) 4 (X = tolyl), 5 24, 11
Both the yields and the 4/5 ratios depend on the amount
of acid and the acid/aldehyde ratio. Indeed, a large excess
of acid together with a twofold excess of aldehyde with re-
spect to the alcohol reactant led to a mixture of 4 and 5 in
a 22:28 ratio and a combined yield of 50% (Table 2, en-
try 1). A decrease of the amount of acid to 3 equiv. was
beneficial to the formation of 4. Under these conditions, 4
was obtained in 28% yield, together with 5 in a 1:1 ratio
(Table 2, entry 2). A further decrease to 2 equiv. of acid
(Table 2, entry 3) gave the best result of a 62% combined
4[c]
5[c]
6[c,d]
7[c,d]
8
In(OTf)3 (3) CH2Cl2
In(OTf)3 (3) toluene
5
61
19
46
42, 13
27
4 (X = tolyl)
InBr3 (2)
TiCl4 (2)
TiCl4 (2)
toluene/CH2Cl2 (3:1) 4 (X = tolyl)
toluene/CH2Cl2 (3:1) 4 (X = Cl), 5
CH2Cl2
4 (X = Cl)
[a] All reactions were carried out at reflux for 15 h with a ratio 3/
alcohol = 2:1. [b] All compounds were purified by silica gel
chromatography. [c] The reaction was carried out in an Ace pres-
sure tube. [d] The reaction was carried out with 1 equiv. of aldehyde
3.
Trifluoroacetic acid (TFA), a Brønsted acid, did not give yield with a clear predominance for product 5. It is interest-
any product. This was consistent with the work of Bang- ing to note that with a 1:1:1 ratio of acid/aldehyde/alcohol
Andersen, who obtained a very poor yield (11%) from the (Table 2, entry 4), a combined 52% yield was observed,
reaction of pyridine-2-carbaldehyde with 3-buten-1-ol in with 5 as the major product. Unfortunately, attempts to use
presence of TFA.[4d] The Lewis acids InCl3 or AlCl3, or a a substoechiometric quantity of acid were unsuccessful. We
combination of TsOH and MgBr2, did not give better re- saw no conversion of the starting material, and no forma-
sults. The use of 3 equiv. of In(OTf)3 (Table 1, entry 1) led tion of 4 or 5 in the crude product (Table 2, entry 5).
2
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Prins and Aza-Prins Cyclisations
Table 2. Influence of the acid/aldehyde/alcohol equivalent ratio.
Compounds 5–12 contain an interesting combination of
one pyridine ring and a partially saturated heterocycle.
Complete reduction of both the heterocyclic alkene and the
pyridine ring would lead to derivatives similar to bispiperid-
ines, which are known to efficiently promote the Henry re-
action.[10] Alternatively, a partial reduction could give pyr-
idyl–piperidine or pyridyl–THP derivatives, as exemplified
below with the synthesis of the alkaloid anabasine.
First, we studied the hydrogenation of the dihydropyran
ring in 5 (Scheme 2). The use of PtO2 (10 mol-%) for 3 h
in EtOAc at room temperature under 1 atm of hydrogen,
selectively gave pyridine–tetrahydropyran bisheterocycle 13
in excellent yield.
Entry[a]
Equiv. In(OTf)3/3/alcohol
Yield 4/5 [%][b]
1
2
3
4
5
4:2:1
3:2:1
2:2:1
1:1:1
0.4:1:1
22:28
28:29
15:47
10:42
–
[a] All reactions were carried out in an Ace pressure tube, in
CH2Cl2 with 3, In(OTf)3, toluene (25 equiv.), and alcohol (1 equiv.)
at 80 °C for 15 h. [b] All compounds were purified by silica gel
chromatography.
We next examined the scope of our method. First, we
investigated the homoallylic alcohol component. Several
homoallylic alcohols were treated with carbaldehyde 3
using a 1:1:2 ratio of In(OTf)3/aldehyde/alcohol in CH2Cl2
at 80 °C in an Ace pressure tube for 15 h (Figure 2). Our
method worked with various homoallylic alcohols to give
products with alkyl chains of various lengths at the position
α to the oxygen atom of the dihydropyran. The use of 4-
penten-2-ol and 1-hepten-4-ol allowed the introduction of
methyl (in 6) and n-propyl (in 7) groups, respectively, in fair
yields.
Scheme 2. Hydrogenation reaction.
When 13 was stirred under H2 (1 atm) in EtOAc in the
presence of PtO2 (10 mol-%) and the reaction was left
longer (6 d), and more catalyst was added after 3 d, we were
able to isolate piperidine–tetrahydropyran derivative 14 in
77% yield. This compound could also be obtained directly
from 5 under identical reaction conditions (69%).
We then applied our method to a very short synthesis
of anabasine, one of the minor alkaloids of the tobacco
plant.[1a,11] As described above, the aza-Prins cyclisation of
pyridine-3-carbaldehyde in the presence of 3-buten-1-amine
led to compound 11 as a mixture of regioisomers. Selective
hydrogenation of 11 gave racemic anabasine in a fair 41%
yield over two steps. This is an appealing sequence com-
pared to the racemic syntheses described in the literature
(Scheme 3).
Figure 2. Variation of the substitution of the heterocycle.
Having shown that the Prins cyclisation was effective
when the pyridine was attached to the aldehyde by a three-
carbon chain, the next challenge was to test whether our
conditions were efficient in the pyridinecarbaldehyde series
(Figure 3). Bisheterocycles 8, 9, and 10 were isolated in 54,
41, and 44% yields respectively, depending on the position
of the aldehyde substituent on the pyridine starting mate-
rial. The method was also effective with a homoallylic
amine, 3-buten-1-amine, and pyridyl–piperidine conjugate
11 could be obtained from pyridine-3-carbaldehyde in 44%
yield.
Scheme 3. Very short synthesis of racemic anabasine.
Conclusions
Figure 3. Variation of the pyridine–heterocycle linkage.
In conclusion, we have shown that the Prins cyclisation
Finally, an appealing double Prins cyclisation was real- can be applied to pyridinic aldehydes, leading to pyridine-
ised using pyridine-2,6-dicarbaldehyde, 3-buten-1-ol containing bisheterocycles. The reaction allowed the con-
(2 equiv.), and Lewis acid (3 equiv.), giving trisheterocycle struction of a variety of cyclic structures. Various carb-
12 in 22% yield.
aldehydes could be used, including dicarbaldehydes. In ad-
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O. Colin, C. Greck, D. Prim, C. Thomassigny
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A), but using titanium tetrachloride instead of indium trifluoro-
methanesulfonate, compound 4 (X = Cl) was obtained as an in-
separable mixture of diastereoisomers a and b (27%). Rf = 0.6
(ethyl acetate). 1H NMR (300 MHz, CDCl3): δ = 8.51 (d, J =
4.7 Hz, 1 H), 7.59 (dd, J = 7.5, 1.3 Hz, 1 H), 7.20–7.08 (m, 2 H),
4.56 (m, 1 Ha), 4.28–4.18 (m, 2 Ha), 4.05–3.79 (m, 2 Hb and 1 Ha),
3.75 (td, J = 12.1, 1.2 Hz, 1 Hb), 3.31–3.23 (m, 1 Hb), 3.00–2.79
(m, 2 H), 2.18–1.54 (m, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 161.5 (Cq), 149.2 (CH), 136.7 (CH), 123.1 (CH), 121.3 (CH),
76.6 (CH), 67.1 (CH2), 62.4 (CH2), 59.9 (CH2), 55.9 (CH), 42.9
(CH2), 39.5 (CH2), 37.2 (CH2), 35.8 (CH2), 34.0 (CH2), 25.8 (CH)
dition, a pyridine–piperidine combination could be ef-
ficiently obtained by using a homoallylic amine instead of
a homoallylic alcohol. Moreover, we showed that a partial
or complete hydrogenation was possible, which increases
the structural variation of the products significantly. Fi-
nally, we succeeded in the synthesis of the alkaloid ana-
basine in a short, fair-yielding, two-step sequence.
Experimental Section
ppm. IR: ν = 3060, 2955, 2923, 2849, 1568, 1474, 1446, 1433, 1077,
˜
General Methods: CH2Cl2 was freshly distilled from calcium
hydride and stored under Ar. Reaction progress was monitored by
thin-layer chromatography (TLC). TLC was carried out using E.
Merck silica gel 60 F254 precoated aluminium plates (0.25 mm),
which were visualised by UV fluorescence quenching or vanillin
staining. Gerudan Si 60 silica gel 60 (40–63 μm) was used for flash
chromatography. 1H NMR spectra were recorded with a Bruker
AV-I 300 MHz spectrometer at 298 K, and were calibrated using
residual CHCl3 (δ = 7.26 ppm). 13C NMR spectra were recorded
with a Bruker Avance 300 spectrometer at 75 MHz and 298 K, and
were calibrated using CDCl3 (δ = 77.16 ppm). 1H NMR spectro-
scopic data are reported as follows: chemical shift δ [ppm] (multi-
plicity, coupling constant [Hz], integration). Multiplicities are re-
ported as follows: s = singlet, d = doublet, t = triplet, dd = doublet
of doublets, td = triplet of doublets, m = multiplet. 13C NMR spec-
troscopic data are reported in terms of chemical shifts δ [ppm]. IR
spectra were obtained with a Nicolet 6700 FTIR spectrometer
using the attenuated total reflectance method, and are reported in
wavenumbers (cm–1). High-resolution mass spectra (HRMS) were
obtained with a Waters Xevo QTOF instrument with an electro-
spray ionisation source (ESI+), using enkephaline leucine as in-
ternal calibrant. Reagents were purchased from Sigma–Aldrich or
Alfa Aesar, and were used as received unless otherwise stated. 3-
(Pyridin-2-yl)propanal 3 was prepared according to a known pro-
cedure.[9]
1049, 749, 561 cm–1. HRMS (ESI+): calcd. for C12H17NOCl [M +
H]+ 226.0999; found 226.1000.
2-{2-[4-(Tolyl)tetrahydro-2H-pyran-2-yl]ethyl}pyridine (4, X = tolyl):
Following the General Procedure for the Prins reaction (work-up
A), but using toluene instead of CH2Cl2, and indium tribromide
instead of indium trifluoromethanesulfonate, compound 4 (X =
tolyl) was obtained as an inseparable mixture of diastereoisomers
and regioisomers (46%). Rf = 0.6 (ethyl acetate). 1H NMR
(300 MHz, CDCl3): δ = 8.52 (d, J = 4.4 Hz, 1 H), 7.58 (t, J =
7.6 Hz, 1 H), 7.22–7.01 (m, 6 H), 4.18–4.12 (m, 1 H), 3.62–3.53 (m,
1 H), 3.43 (m, 1 H), 3.03–2.68 (m, 3 H), 2.34 (s, 3 H), 1.94 (m, 2
H), 1.85–1.65 (m, 3 H), 1.56–1.44 (m, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 162.0 (Cq), 149.3 (CH), 145.8 (Cq), 143.6
(Cq), 142.9 (Cq), 138.1 (Cq), 136.4 (CH), 135.8 (Cq), 135.1 (Cq),
130.5–121.1 (CH), 77.6 (CH), 68.4 (CH2), 68.3 (CH2), 41.7–32.9
(CH ), 21.5 (CH ), 21.0 (CH ), 19.4 (CH ) ppm. IR: ν = 3047,
˜
2
3
3
3
3009, 2927, 2916, 2839, 1568, 1473, 1433, 1126, 1083, 1050, 992,
806, 750, 725 cm–1. HRMS (ESI+): calcd. for C19H24NO [M +
H]+ 282.1858; found 282.1861.
2-[2-(Dihydro-2H-pyran-2-yl)ethyl]pyridine (5): Following the Gene-
ral Procedure for the Prins reaction (work-up A), compound 5 was
obtained as an inseparable mixture of regioisomers a and b (61%).
1
Rf = 0.5 (ethyl acetate). H NMR (300 MHz, CDCl3): δ = 8.50 (d,
J = 4.6 Hz, 1 H), 7.56 (td, J = 7.7, 1.8 Hz, 1 H), 7.15 (d, J = 7.8 Hz,
1 H), 7.08 (t, J = 5.4–6.8 Hz, 1 H), 5.82–5.61 (m, 2 H), 4.16 (d, J
= 2.0 Hz, 2 Ha), 4.10 (s, 1 Hb), 3.96 (m, 1 Hb), 3.64 (s, J = 9.81 Hz,
1 Hb), 3.51–3.42 (m, 1 Ha), 3.01–2.81 (m, 2 H), 2.06–1.86 (m, 4 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 161.9 (Cq), 149.2 (CH),
136.5 (CH), 130.3 (CH), 126.4 (CH), 125.1 (CH), 123.1 (CH), 121.1
(CH), 73.1 (CH), 73.0 (CH), 66.0 (CH2), 63.4 (CH2), 35.8 (CH2),
Prins Reaction. General Procedure: The carbonyl compound
(1 equiv.) was dissolved in dry CH2Cl2 (2.8 mL) in an Ace pressure
tube (diameter: 1.3 cm, height: 10.5 cm). The homoallylic alcohol
(1 equiv.) was added under an argon atmosphere. Indium trifluoro-
methanesulfonate (2 equiv.) was then added, and the reaction mix-
ture was stirred at 80 °C for 15 h.
Work-up Procedure A: The reaction mixture was quenched with
sodium hydrogen carbonate (saturated aq.; 5 mL), and the aqueous
layer was extracted with ethyl acetate (4ϫ 5 mL). The combined
organic extracts were dried with magnesium sulfate, and the solvent
was removed in vacuo. The residue was purified by flash
chromatography (pentane/ethyl acetate, 4:1) to give the expected
product.
35.2 (CH ), 34.2 (CH ), 31.1 (CH ); 25.4 (CH ) ppm. IR: ν = 3031,
˜
2
2
2
2
2920, 2842, 2827, 1565, 1472, 1433, 1179, 1083, 766, 747, 647 cm–1.
HRMS (ESI+): calcd. for C12H16NO [M + H]+ 190.1232; found
190.1236.
2-[2-(6-Methyldihydro-2H-pyran-2-yl)ethyl]pyridine (6): Following
the General Procedure for the Prins reaction (work-up A), com-
pound 6 was obtained as an inseparable mixture of diastereoiso-
mers and regioisomers (43%). Rf = 0.3 (ethyl acetate). 1H NMR
(300 MHz, CDCl3): δ = 8.51 (d, J = 6.4 Hz, 1 H), 7.57 (td, J =
11.4, 2.7 Hz, 1 H), 7.19–7.05 (m, 2 H), 5.82–5.77 (m, 1 H), 5.66–
5.61 (m, 1 H), 4.17 (s, 1 H), 3.88–3.20 (s, 1 H), 2.92 (m, 2 H), 2.00–
1.90 (m, 4 H, CH2), 1.29–1.03 (m, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 149.6 (CH), 149.3 (CH), 136.6 (CH), 136.4 (CH), 123.0
(CH), 121.7 (CH), 104.4 (CH), 76.0 (CH), 74.6 (CH), 42.8 (CH2),
Work-up Procedure B: The solvent was removed in vacuo, and the
residue was purified by flash chromatography [CH2Cl2/MeOH/am-
monia (30% in water), 100:0.1:2] to give the expected product.
Hydrogenation Reaction. General Procedure: A solution of dihydro-
pyran 5 or tetrahydropyran 13 (1 equiv.) in ethyl acetate (2 mL)
containing platinium oxide (80% PtO2; 10 mol-%) was hydroge-
nated (pH2 = 1 atm) at room temperature for 3 h. The mixture was
filtered through a pad of Celite, and the solvent was removed in
vacuo. The residue was purified by flash chromatography [CH2Cl2/
MeOH/ammonia (30% in water), 100:0.1:2] to give the expected
product.
34.8 (CH ), 34.6 (CH ), 34.4 (CH ), 20.6 (CH ) ppm. IR: ν = 2965,
˜
2
2
2
3
2928, 2860, 1662, 1568, 1474, 1434, 1335, 1242, 1198, 1149, 1081,
1042, 993, 750 cm–1. HRMS (ESI+): calcd. for C13H18NO [M +
H]+ 204.1388; found 204.1388.
2-[2-(4-Chlorotetrahydro-2H-pyran-2-yl)ethyl]pyridine (4, X = Cl):
2-[2-(6-Propyldihydro-2H-pyran-2-yl)ethyl]pyridine (7): Following
Following the General Procedure for the Prins reaction (work-up
the General Procedure for the Prins reaction (work-up A), com-
4
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Prins and Aza-Prins Cyclisations
pound 7 was obtained as an inseparable mixture of diastereoiso-
mers and regioisomers (50%). Rf = 0.8 (ethyl acetate). 1H NMR
(300 MHz, CDCl3): δ = 8.51 (d, J = 4.1 Hz, 1 H), 7.60 (dd, J =
7.7, 6.0 Hz, 1 H), 7.20 (d, J = 7.7 Hz, 1 H), 7.11 (t, J = 5.3–7.0 Hz,
1 H), 5.81–5.77 (m, 1 H), 5.64–5.61 (m, 1 H), 4.10 (m, 1 H), 3.50–
3.46 (m, 1 H), 3.03–2.86 (m, 2 H), 2.00–1.87 (m, 4 H), 1.51–1.35
5.84 (s, 1 Ha), 5.17–5.08 (m, 1 Ha), 4.16–4.02 (m, 1 Ha), 3.89 (t, J
= 10.6 Hz, 1 H), 3.68–3.33 (m, 2 Ha and 1 Hb), 3.09–2.98 (m, 1
Hb), 2.46–2.25 (m, 2 H), 1.81 (s, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 149.1 (CH), 148.9 (CH), 148.6 (CH), 139.9 (Cq), 135.5
(CH), 134.2 (CH), 126.3 (CH), 125.2 (CH), 123.6 (CH), 118.4
(CH), 56.0 (CH), 55.4 (CH), 46.0 (CH2), 44.0 (CH2), 41.5 (CH2),
(m, 4 H), 0.92–0.87 (m, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ 34.0 (CH ) ppm. IR: ν = 3268, 3029, 2912, 2829, 1577, 1477, 1424,
˜
2
= 162.0 (Cq), 148.8 (CH), 136.8 (CH), 130.8 (CH), 130.4 (CH), 1099, 1026, 804, 713 cm–1. HRMS (ESI+): calcd. for C10H13N2
125.3 (CH), 124.6 (CH), 123.4 (CH), 121.2 (CH), 74.1 (CH), 73.8 [M + H]+ 161.1079; found 161.1080.
(CH), 41.6 (CH2), 38.4 (CH2), 35.9 (CH2), 35.5 (CH2), 34.2 (CH2),
2,6-Bis(dihydro-2H-pyran-2-yl)pyridine (12): Following the General
33.8 (CH2), 32.0 (CH2), 31.5 (CH2), 18.9 (CH2), 14.3 (CH3) ppm.
Procedure for the Prins reaction (work-up B), but using 2 equiv.
IR: ν = 3025, 3009, 2956, 2927, 2870, 1569, 1473, 1457, 1433, 1183,
˜
of homoallylic alcohol instead of 1 equiv., and 3 equiv. of indium
trifluoromethanesulfonate instead of 2 equiv., compound 12 was
obtained as an inseparable mixture of diastereoisomers and re-
gioisomers (22%). Rf = 0.9 [CH2Cl2/MeOH/ammonia (30% in
water), 100:10:2]. 1H NMR (300 MHz, CDCl3): δ = 7.73 (t, J =
7.7 Hz, 1 H), 7.38 (d, J = 7.7 Hz, 2 H), 6.03–5.78 (m, 4 H), 5.26
(s, 2 H), 4.69–4.64 (m, 2 H), 4.39 (s, 4 H), 4.20–4.05 (m, 2 H), 3.88
(td, J = 9.4, 4.0 Hz, 2 H), 2.49–2.28 (m, 4 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 160.8 (Cq), 137.6 (CH), 126.3 (CH), 124.6
1080, 1050, 993, 769, 748 cm–1. HRMS (ESI+): calcd. for
C15H22NO [M + H]+ 232.1701; found 232.1695.
2-(Dihydro-2H-pyran-2-yl)pyridine (8): Following the General Pro-
cedure for the Prins reaction (work-up B), compound 8 was ob-
tained as an inseparable mixture of regioisomers a and b (54%). Rf
= 0.6 [CH2Cl2/MeOH/ammonia (30% in water), 100:10:2]. 1H
NMR (300 MHz, CDCl3): δ = 8.55 (d, J = 4.7 Hz, 1 H), 7.70 (t, J
= 7.6 Hz, 1 H), 7.48 (d, J = 7.8 Hz, 1 H), 7.19 (m, 1 H), 5.99–5.79
(m, 2 H), 5.27 (m, 1 Hb), 4.68 (dd, J = 9.9, 3.5 Hz, 1 Ha), 4.39 (s,
2 Ha), 4.11–4.07 (m, 1 Hb), 3.91–3.87 (m, 1 Hb), 2.50–2.31 (m, 2
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 161.6 (Cq), 149.1 (CHb),
148.8 (CHa), 137.0 (CH), 128.8 (CHb), 126.2 (CHa), 125.3 (CHb),
124.4 (CHa), 122.5 (CH), 121.0 (CHb), 120.3 (CHa), 77.0 (CHb),
(CH), 118.9 (CH), 77.4 (CH), 66.7 (CH ), 31.7 (CH ) ppm. IR: ν
˜
2
2
= 3034, 2925, 2829, 1578, 1458, 1240, 1179, 1088, 1023, 994, 808,
752 cm–1. HRMS (ESI+): calcd. for C15H18NO2 [M
244.1338; found 244.1341.
+
H]+
2-[2-(Tetrahydro-2H-pyran-2-yl)ethyl]pyridine (13): Following the
General Procedure for the hydrogenation reaction, compound 13
was obtained (90%). Rf = 0.5 [CH2Cl2/MeOH/ammonia (30% in
water), 100:10:2]. 1H NMR (300 MHz, CDCl3): δ = 8.51 (d, J =
4.5 Hz, 1 H), 7.61 (t, J = 7.7 Hz, 1 H), 7.18 (d, J = 7.8 Hz, 1 H),
7.12 (t, J = 6.0–6.4 Hz, 1 H), 3.97 (d, J = 11.2 Hz, 1 H), 3.39 (td,
J = 11.3, 2.8 Hz, 1 H), 3.29–3.21 (m, 1 H), 2.96–2.85 (m, 2 H),
1.90–1.78 (m, 2 H), 1.62–1.24 (m, 6 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 162.0 (Cq), 148.8 (CH), 136.9 (CH), 123.3 (CH), 121.2
(CH), 77.1 (CH), 68.6 (CH2), 36.5 (CH2), 34.1 (CH2), 32.0 (CH2),
76.3 (CHa), 66.6 (CH2a), 63.6 (CH2b), 31.4 (CH2a), 25.1 (CH2b
)
ppm. IR: ν = 3028, 2930, 2892, 2827, 1726, 1571, 1473, 1435, 1239,
˜
1180, 1087, 1024, 994, 780, 754 cm–1. HRMS (ESI+): calcd. for
C10H12NO [M + H]+ 162.0919; found 162.0918.
3-(Dihydro-2H-pyran-2-yl)pyridine (9): Following the General Pro-
cedure for the Prins reaction (work-up B), compound 9 was ob-
tained as an inseparable mixture of regioisomers (41%). Rf = 0.6
[CH2Cl2/MeOH/ammonia (30% in water), 100:10:2]. 1H NMR
(300 MHz, CDCl3): δ = 8.59 (s, 1 H), 8.50 (m, 1 H), 7.70 (m, 1 H),
7.26 (m, 1 H), 5.95–5.88 (m, 1 H), 5.82–5.76 (m, 1 H), 4.64–4.62
(m, 1 H), 4.29 (s, 2 H), 2.29 (s, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 149.0 (CH), 147.9 (CH), 138.0 (Cq), 133.6 (CH), 126.6
(CH), 124.0 (CH), 123.5 (CH), 73.4 (CH), 66.6 (CH2), 32.7 (CH2)
26.3 (CH ), 23.6 (CH ) ppm. IR: ν = 3062, 2922, 2849, 1568, 1473,
˜
2
2
1434, 1095, 1046, 769, 478 cm–1. HRMS (ESI+): calcd. for
C12H18NO [M + H]+ 192.1388; found 192.1384.
2-[2-(Tetrahydro-2H-pyran-2-yl)ethyl]piperidine (14): Following the
General Procedure for the hydrogenation reaction, but running the
reaction for 6 d instead of 3 h, compound 14 was obtained (77%).
Rf = 0.1 [CH2Cl2/MeOH/ammonia (30% in water), 100:10:2]. 1H
NMR (300 MHz, CDCl3): δ = 3.95 (d, J = 11.2 Hz, 1 H), 3.40 (t,
J = 11.0 Hz, 1 H), 3.27–3.13 (m, 1 H), 3.06 (d, J = 11.8 Hz, 1 H),
2.61 (t, J = 11.6 Hz, 1 H), 2.49–2.36 (m, 1 H), 2.05–0.97 (m, 17 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 78.2 (CH), 68.7 (CH2), 57.1
(CH), 47.2 (CH2), 33.4 (CH2), 33.2 (CH2), 32.8 (CH2), 32.0 (CH2),
ppm. IR: ν = 3035, 2924, 2893, 2827, 1578, 1424, 1177, 1086, 1023,
˜
900, 804, 713 cm–1. HRMS (ESI+): calcd. for C10H12NO [M +
H]+ 162.0919; found 162.0915.
4-(Dihydro-2H-pyran-2-yl)pyridine (10): Following the General Pro-
cedure for the Prins reaction (work-up B), compound 10 was ob-
tained as an inseparable mixture of regioisomers a and b (44%). Rf
= 0.6 [CH2Cl2/MeOH/ammonia (30% in water), 100:10:2]. 1H
NMR (300 MHz, CDCl3): δ = 8.54 (d, J = 5.5 Hz, 2 H), 7.27 (d,
J = 5.5 Hz, 2 H), 5.90–5.73 (m, 2 H), 5.11 (s, 1 Hb), 4.53 (dd, J =
9.3, 4.6 Hz, 1 Ha), 4.34 (s, 2 Ha), 4.01–3.94 (m, 1 Hb), 3.84–3.75
(m, 1 Hb), 2.25 (m, 2 Hb); 2.25 (m, 2 Ha) ppm. 13C NMR (75 MHz,
CDCl3): δ = 151.5 (Cq), 150.0 (CH), 149.9 (CH), 128.2 (CH), 126.6
(CH), 126.2 (CH), 123.9 (CH), 121.9 (CH), 120.7 (CH), 74.6 (CH),
74.0 (CH), 66.4 (CH2), 63.3 (CH2), 32.5 (CH2), 25.0 (CH2) ppm.
26.6 (CH ), 26.3 (CH ), 24.9 (CH ), 23.7 (CH ) ppm. IR: ν = 3300,
˜
2
2
2
2
2925, 2846, 1439, 1328, 1260, 1088, 1049, 880, 728 cm–1. HRMS
(ESI+): calcd. for C12H23NO [M + H]+ 198.1858; found 198.1858.
(؎)-Anabasine: Following the General Procedure for the hydrogen-
ation reaction starting from compound 11, racemic anabasine was
obtained (93%). Analytical and spectroscopic data were in agree-
ment with those reported in the literature.[11e] HRMS (ESI+): calcd.
for C10H15N2 [M + H]+ 163.1235; found 163.1238.
IR: ν = 3033, 2926, 2892, 2828, 1410, 1180, 1088, 1024, 992, 858,
˜
814, 758, 614 cm–1. HRMS (ESI+): calcd. for C10H12NO [M +
H]+ 162.0919; found 162.0917.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR spectra for all new com-
pounds.
3-(Dihydro-2H-piperidinen-2-yl)pyridine (11): Following the Gene-
ral Procedure for the Prins reaction (work-up B), but using 3-buten-
1-amine instead of homoallylic alcohol, compound 11 was ob-
tained as an inseparable mixture of regioisomers a and b (44%). Rf
= 0.6 [CH2Cl2/MeOH/ammonia (30% in water), 100:10:2]. 1H
Acknowledgments
NMR (300 MHz, CDCl3): δ = 8.64–8.58 (m, 1 H), 8.53–8.50 (m, 1 The authors are grateful to the Centre National de la Recherche
H), 7.80–7.68 (m, 1 H), 7.30–7.24 (m, 1 H), 5.98–5.67 (m, 2 Hb), Scientifique (CNRS), the University of Versailles Saint Quentin-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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Job/Unit: O42971
/KAP1
Date: 15-09-14 11:04:16
Pages: 7
O. Colin, C. Greck, D. Prim, C. Thomassigny
FULL PAPER
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2013, 19, 857–860.
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(ANR-11-BS07-030-01) for the financial support and a grant to
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[3]
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Received: July 22, 2014
Published Online: ᭿
6
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42971
/KAP1
Date: 15-09-14 11:04:16
Pages: 7
Prins and Aza-Prins Cyclisations
Prins Reactions
O. Colin, C. Greck, D. Prim,
C. Thomassigny* ............................... 1–7
Toward Pyridine–Heterocycle Patterns
through Prins and Aza-Prins Cyclisations:
Application to a Short Synthesis of (Ϯ)-
Anabasine
The (aza)-Prins cyclisation has been ap-
plied to several pyridine carbaldehydes,
opening the way to an easy access to
bisheterocycles. The method was effective
for the synthesis of anabasine in two steps.
Keywords: Nitrogen heterocycles / Oxygen
heterocycles / Natural products / Cycli-
zation / Hydrogenation / Prins reaction
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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