Expedient synthesis of 3-substituted-1,2,3,6-tetrahydropyridines

Article abstract of DOI:10.1016/j.tetlet.2011.08.112

The treatment of alkyl or aryl halides with an excess of tetrakis(pyridine)lithium tetrakis(N-dihydropyridyl)aluminate affords the corresponding 3-substituted-1,2,3,6-tetrahydropyridines in moderate to good yields via a tandem alkylation-reduction reactio

Full text of DOI:10.1016/j.tetlet.2011.08.112

Tetrahedron Letters 52 (2011) 5940–5942
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Expedient synthesis of 3-substituted-1,2,3,6-tetrahydropyridines
⇑
Lilian Alcaraz, Bertrand Coquebert de Neuville, Andrew Lister, Bryan Roberts
Department of Chemistry, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leics LE11 5RH, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
The treatment of alkyl or aryl halides with an excess of tetrakis(pyridine)lithium tetrakis(N-dihydropyr-
idyl)aluminate affords the corresponding 3-substituted-1,2,3,6-tetrahydropyridines in moderate to good
yields via a tandem alkylation–reduction reaction.
Received 28 June 2011
Revised 8 August 2011
Accepted 19 August 2011
Available online 5 September 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Landsbury’s reagent
Reduction
Alkylation
Tetrahydropyridine
Tetrakis(pyridine)lithium tetrakis(N-
dihydropyridyl)aluminate
Tetrakis(pyridine)lithium tetrakis(N-dihydropyridyl)aluminate
(1) which can be prepared by the reaction of lithium aluminium
hydride and pyridine is known as Landsbury’s reagent and was first
reported in 1963.1 A number of publications have subsequently
discussed both the structure and reactivity of 1.2,3 Notably, the
structure of lithium tetrakis(N-dihydropyridyl)aluminate (LDPA)
originally suggested by Landsbury was more recently reassigned
by Hensen et al. as 1 in which the counterion has been character-
ized as tetrakis(pyridine)lithium as opposed to lithium.3c
significant challenge in organic chemistry.7 As a continuation of
this work, we report here a general methodology for the rapid
preparation of a range of novel 3-substituted-1,2,3,6-tetrahydro-
pyridines which could either be synthetically valuable intermedi-
ates or compounds of biological interest.7,8
Our strategy was as outlined in Scheme 1. As described above, it
has been reported that 1 can react with a halide to form 2,5-dihy-
dropyridine intermediate 2 that is then oxidized in situ and aroma-
tized to the corresponding 3-substituted pyridine 3.4 We wondered
if we could reduce the rate of the oxidation step and utilize the
mild reducing properties of 1 to convert 2 into the desired 3-
substituted-1,2,3,6-tetrahydropyridine 4. Although working in
low yield, a related reaction involving methylpyridinium iodide,
lithium aluminium hydride and salicylaldehyde had been previ-
ously described in the literature which gave us the impetus to pur-
sue this approach.9
H
-
H
1 equiv. LiAlH4
pyridine
+
N
N
4
LiPy4
N
Al
H
H
m
n
1
m + n = 4
Complex 1 was shown to be a milder reducing agent than lith-
ium aluminium hydride and to only react with very electrophilic
carbonyl compounds by hydrogen or electron transfer from one
of the dihydropyridine goups.2 The alkylating properties of 1 were
later discovered and successfully applied by Giam to the direct
synthesis of 3-substituted pyridines.4 Although an interesting
transformation, we were only able to find one example of its use
in synthetic chemistry.5 During the course of a medicinal chemis-
try programme aimed at the discovery of novel P2X7 receptor
antagonists, we became interested in the preparation of 3-substi-
tuted piperidines.6 The synthesis of these systems, especially when
additionally functionalized on the piperidine ring, still represents a
R
R
R
1
[O]
Br
-10 ºC-0 ºC
N
N
2
3
1
RT
R
NH
4
⇑
Corresponding author. Tel.: +44 (0) 1625 582828; fax: +44 (0) 1625 583074.
E-mail address: bryan.roberts@astrazeneca.com (B. Roberts).
Scheme 1. Synthesis of 3-substituted-1,2,3,6-tetrahydropyridine 4 through tan-
dem alkylation-reduction of halides.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.112

L. Alcaraz et al. / Tetrahedron Letters 52 (2011) 5940–5942
5941
Ar
Ar
also found that the reaction of reagent 1 with the halide at room
temperature increased the rate of the reduction step and mini-
mized the formation of pyridine 6 whereas the reactions main-
tained between À10 and 0 °C favored the formation of 6. It was
demonstrated that 6–8 equiv of 1 were optimal for the formation
of 5 with higher excess leading to increasing the formation of ha-
lide reduction product 8. In all cases some levels of side products
6 (1–10%), over-alkylated compound 7 (5–8%) and reduced halide
8 (1–9%) were observed.10 Isolation of 5 from the reaction mixture
was optimally achieved by the addition of sodium hydroxide fol-
lowed by in situ treatment of the crude reaction mixture with di-
tert-butyl dicarbonate.11
With optimized conditions in hand the scope of this methodol-
ogy was explored (Table 1).12 Exposure of a range of halides to
6 equiv of 1 at room temperature in pyridine followed by in situ
protection with di-tert-butyl dicarbonate resulted in moderate to
good yields of the corresponding tert-butyl carbamate protected
3-substituted-1,2,3,6-tetrahydropyridines (entries 1–15). For the
Ar
NH
N
Br
1
N
5
6
Ph
Ar
Me
Ar
7
8
Ar
Scheme 2. Model system: 3-substituted-1,2,3,6-tetrahydropyridine 5 and observed
side-products.
A model reaction was investigated (Scheme 2) paying particular
attention at degassing of the solvents, reaction temperature, and
stoichiometry of the reagents on the outcome of the reaction. It
was found that reagent 1 was best prepared by careful addition
of solid lithium aluminium hydride to a freshly distiled solution
of pyridine under nitrogen, in order to minimize the oxygen con-
tent of the solution, and aged for 20 h at room temperature. We
Table 1
Tandem alkylation–reduction of aryl and alkyl halides by reaction with 112
Entry
1
Substrate
Product
Yielda (%)
72
Br
NBoc
Br
Br
NBoc
2
3
4
5
53
61
52
43
Cl
Cl
NBoc
NBoc
Br
Br
Br
F3C
F3C
Br
NBoc
MeO
NC
MeO
NC
6
7
8
a- ortho
b- meta
53
61
45
NBoc
Br
c- para
Br
NBoc
9
40
CO2Me
Me
CO2Me
Me
10
11
59b
68
Br
NBoc
Ph
Br
Ph
NBoc
Br
NBoc
NBoc
12
13
53
46
Br
I
14
15
58
55
NBoc
I
NBoc
a
Isolated yield.
1:1 Diastereoisomeric mixture.
b

5942
L. Alcaraz et al. / Tetrahedron Letters 52 (2011) 5940–5942
3. (a) Tanner, D. D.; Yang, C. M. J. Org. Chem. 1993, 58, 1840–1846; (b) Tanner, D.
D.; Yang, C. M. J. Org. Chem. 1993, 58, 5907–5914; (c) Hensen, K.; Lemke, A.;
Stumpf, T.; Bolte, M.; Fleischer, H.; Pulham, C. R.; Gould, R. O.; Harris, S. Inorg.
Chem. 1999, 38, 4700–4704.
4. Giam, C.-S.; Abbott, S. D. J. Am. Chem. Soc. 1971, 93, 1294–1296.
5. Ohshima, E.; Sato, H.; Obase, H.; Miki, I.; Ishii, A.; Kawakage, M.; Shirakura, S.;
Karasawa, A.; Kubo, K. J. Med. Chem. 1993, 36, 1613–1618.
6. Furber, M.; Alcaraz, L.; Bent, J. E.; Beyerbach, A.; Bowers, K.; Braddock, M.;
Caffrey, M. V.; Cladingboel, D.; Collington, J.; Donald, D. K.; Fagura, M.; Ince, F.;
Kinchin, E. C.; Laurent, C.; Lawson, M.; Luker, T. J.; Mortimore, M. M. P.; Pimm,
A. D.; Riley, R. J.; Roberts, N.; Robertson, M.; Theaker, J.; Thorne, P. V.; Weaver,
R.; Webborn, P.; Willis, P. J. Med. Chem. 2007, 50, 5882–5885.
7. (a) Morton, D.; Leach, S.; Cordier, C.; Warriner, S.; Nelson, A. Angew. Chem., Int.
Ed. 2009, 48, 104–109; (b) Mihara, Y.; Ojima, H.; Imahori, T.; Yoshimura, Y.;
Ouchi, H.; Takahata, H. Heterocycles 2007, 72, 633–645; (c) Banfi, L.; Guanti, G.;
Paravidino, M.; Riva, R. Org. Biomol. Chem. 2005, 3, 1729–1737; (d) Sakagami,
H.; Ogasawara, K. Heterocycles 2001, 54, 43–47; (e) Jakobsen, P.; Lundbeck, J.
M.; Kristiansen, M.; Breinholt, J.; Demuth, H.; Pawlas, J.; Torres Candela, M. P.;
Andersen, B.; Westergaard, N.; Lundgren, K.; Asano, N. Bioorg. Med. Chem. 2001,
9, 733–744; (f) Knapp, S.; Zhao, D. Org. Lett. 2000, 2, 4037–4040; (g) Hansen, S.
U.; Bols, M. J. Chem. Soc., Perkin Trans. 1 2000, 911–915; (h) Schleich, S.;
Helmchen, G. Eur. J. Org. Chem. 1999, 2515–2521; (i) Reimann, E.; Speckbache, J.
Arch. Pharm. 1990, 323, 13–15; (j) Imanishi, T.; Shin, H.; Yagi, N.; Hanaoka, M.
Tetrahedron Lett. 1980, 21, 3285–3288.
benzyl bromides, a range of functional groups (entries 2–9) and
substitution patterns were well tolerated (entries 6–8). More hin-
dered benzylic systems also performed well under the reaction
conditions (entries 10 and 11). Other activated systems such as al-
lyl (entry 12) or propargyl (entry 13) afforded the desired products
in good yields. Finally, the alkyl systems required a switch to iodide
in order that the reaction takes place in reasonable yield (entries
14 and 15). It is probably worth noting that the apparent higher
yield for the model reaction (entry 1) would seem to indicate that
yields could be further optimized individually for other substrates.
In order to demonstrate the possibility of removing the tert-bu-
tyl carbamate protecting group, examples of compounds from
\Table 1 (entries 1, 10, 11 and 12) were treated with HCl in iso-pro-
panol to yield the corresponding amines as hydrochloride salts in
quantitative yields.13
In summary, we have developed a simple and novel direct syn-
thesis of 3-substituted-1,2,3,6-tetrahydropyridines from pyridine
and readily accessible halides using Landsbury’s reagent. Although
yields are moderate, this one-step procedure is efficient and leads
to synthetically valuable intermediates7 or compounds of biologi-
cal interest.8 Further work in this area will focus on an enantiose-
lective version using chiral auxiliaries as well as exploring other
heterocyclic systems.
8. Pei, Y.; Arbor, A.; Tecle, H. (Warner Lambert Company). US Patent 5,208,343,
May 4, 1993. Chem. Abstr. 1993, 119, 160124.
9. Onaka, T. Tetrahedron Lett. 1971, 46, 4395–4398.
10. Ratios were determined by HPLC/MS and were not corrected for differences in
absorption of the individual components of the crude reaction mixture. We
have also noticed that the ratios can be dependent on the batch of LAH used
and that more consistent results were obtained with freshly opened samples.
Aldrich, reagent grade, LAH >97% pure packed in plastic bags was used during
the course of this work and no other sources were studied.
Acknowledgements
11. Although not isolated, it is likely that during workup the excess Landsbury’s
reagent is hydrolysed to the a mixture of 1,4-, 1,2-, and 2,5-dihydropyridines
(DHPs) that has been shown to be stable in the absence of oxygen.3a Mixtures
of 1,2- and 2,5-DHPs left to stand in the presence of oxygen can then undergo
base-catalysed condensation to yield ( )-anatabine that can further evolve to
( )-anabasine (Yang, C.-M.; Tanner, D. Can. J. Chem. 1997, 75, 616–620).
12. General procedure: Freshly opened solid lithium aluminium hydride (6.0 mmol)
was very cautiously added to freshly distiled pyridine (12 mL) at 0 °C in
portions under an N2 atmosphere, and the mixture was stirred at room
temperature for 20 h. (Caution: This is an exothermic reaction.) Electrophile
(1.0 mmol, either neat or in 2 mL of dry degassed THF) was added and the
mixture was stirred at room temperature for 2 h. The resulting mixture was
cautiously quenched with MeOH (25 mL), basified with 15% aqueous NaOH
(0.2 mL) and evaporated. The residue was azeotroped with toluene
(2 Â 40 mL), dissolved in Et2O (60 mL), dried over Na2SO4 and stirred for
30 min. Di-tert-butyl dicarbonate (1.4 mmol) was added and the mixture was
stirred overnight, filtered then evaporated. The resulting residue was purified
by flash silica gel chromatography eluting with EtOAc and iso-hexane to afford
the desired compound.
We are grateful to Sara Duncan and Hema Pancholi from the
department of Analytical Sciences at AstraZeneca Charnwood for
their expert assistance in MS studies. We also thank Dr. Tim Luker
and Dr. Andrew Morley from the Department of Medicinal Chem-
istry at AstraZeneca Charnwood for helpful suggestions on this
manuscript.
Supplementary data
Supplementary data (representative experimental procedures
and compound characterisation data) associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2011.08.112.
13. General procedure: Tert-butyl tetrahydropyridine carboxylates (0.4 mmol) were
dissolved in MeOH (1 mL) and a 6 M solution of HCl in i-PrOH (1 mL) was
added. The resulting mixture was stirred overnight then evaporated to give the
hydrochloride salts as off-white solids or oils.
References and notes
1. Lansbury, P. T.; Peterson, J. O. J. Am. Chem. Soc. 1963, 85, 2236–2242.
2. (a) Lansbury, P. T.; MacLeay, R. E. J. Am. Chem. Soc. 1965, 87, 831–837; (b)
Mantescu, C.; Genunche, A. Tetrahedron Lett. 1966, 46, 5675–5678; (c) Ashby, E.
C.; Goel, A. B. J. Org. Chem. 1981, 46, 3934–3936.