An efficient synthesis of 2-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)morpholine: a potent M1 selective muscarinic agonist

Article abstract of DOI:10.1016/j.tetlet.2007.04.135

2-(1-Methyl-1,2,5,6-tetrahydropyridin-3-yl)morpholine is useful for synthesizing potent antimicrobials including the arecoline derivatives, phendimetrazine and polygonapholine and was synthesised in nine steps with an overall yield of 36%. Bromination of

Full text of DOI:10.1016/j.tetlet.2007.04.135

Tetrahedron Letters 48 (2007) 4565–4568
An efficient synthesis of
2-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)morpholine: a potent
M1 selective muscarinic agonist
Y. C. Sunil Kumar, M. P. Sadashiva and K. S. Rangappa*
Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570 006, India
Received 9 March 2007; revised 17 April 2007; accepted 26 April 2007
Available online 1 May 2007
Abstract—2-(1-Methyl-1,2,5,6-tetrahydropyridin-3-yl)morpholine is useful for synthesizing potent antimicrobials including the arec-
oline derivatives, phendimetrazine and polygonapholine and was synthesised in nine steps with an overall yield of 36%. Bromination
of 3-acetylpyridine and dehydration of a diol with cyclization were pivotal to the success of the strategy.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Neurochemical examination of the brain material from
Alzheimer’s patients has demonstrated loss of the pre-
synaptic marker enzyme choline acetyltransferase and
the muscarinic receptors of the M2 subtype which are
mainly responsible in causing deficits in central choliner-
gic transmission in Alzheimer’s patients.1–3 The postsyn-
aptic muscarinic receptors, which primarily are of the
M1 subtype, to a large extent, seem to survive the loss
of cholinergic nerve endings.4 These findings have led
to attempts at restoring cholinergic function by means
of cholinomimetic drugs such as acetylcholinesterase
inhibitors and muscarinic agonists, the hypothesis being
that enhancement of cholinergic neurotransmission
would alleviate the symptoms of the diseases, particu-
larly the deficits in cognition and memory.4 Pharmaco-
logical investigation of muscarinic receptor subtypes
using both functional and binding studies has identified
three distinct muscarinic receptor5 subtypes, M1, M2
and M3. Identifying M1 selective muscarinic agonists
which are capable of crossing the blood–brain barrier
is the subject of active research for pharmacological
application.6 Arecoline 1, an alkaloid obtained from
the betel nut (Areca catechu), the fruit of a palm tree,
has been used previously as a leading structure to design
centrally active muscarinic agents.7 The lack of M1
selectivity and efficacy due to dose limiting side effects
associated with M2 and M3 muscarinic receptor subtype
stimulation have produced disappointing results.7
Replacement of the ester functionality of arecoline with
either the 3-alkyl-1,2,4-oxadiazole 2 or the 3-alkyl-1,2,4-
thiadiazole 3 has produced very potent muscarinic
agonists.8,9
However, the systematic removal of a heteroatom in the
3-methyl-1,2,4-oxadiazole giving oxazoles and furans
caused a decrease in affinity for the agonist binding site.
The two isomers, 2-methyl-1,2,4-oxadiazole 4 and 5-
methyl-1,2,4-oxadiazole 5 also had lower affinities for
muscarinic receptors.8,9 No muscarinic M1 subtype
selectivity has been reported for 2-(1-methyl-1,2,5,6-tet-
rahydropyridin-3-yl)morpholine 13. C-Functionalized
morpholines are found in a variety of natural products
and biologically active compounds. Since compound
13 is a conformationally restricted arecoline analogue
we were encouraged to pursue this compound. Further-
more sulfonylation, amidation and alkylation on the
nitrogen atom of the morpholine ring would provide
analogues for biological evaluation (see Fig. 1).
C-Functionalized morpholines are found in various
naturally occurring products as well as in drugs
but,10 synthetic access is rather restricted since morphol-
ines are often derived from aminoalcohols11a and
aminoepoxides.11b A retrosynthetic analysis of this gen-
eral target structure leads to an enantiopure epoxide
and an aminoalcohol as the starting materials (see
Fig. 2).
Keywords: C-Substituted morpholines; 2-Acetyl pyridine; Arecoline.
*
Corresponding author. Tel./fax: +91 821 2412191; e-mail addresses:
rangappaks@yahoo.com; rangappaks@chemistry.uni-mysore.ac.in
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.135

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Y. C. Sunil Kumar et al. / Tetrahedron Letters 48 (2007) 4565–4568
O
nyl pyridine gave the N-oxide,12 and dihydroxylation of
N
S
N
O
the vinyl pyridine gave the dihydroxylated compound
which was highly water soluble. The starting material
3-vinyl pyridine, moreover, undergoes polymerization
very quickly.13 Here we report a novel, efficient and con-
cise synthetic strategy to prepare 2-pyridyl substituted
morpholines.
R
R
OMe
N
N
N
N
N
CH3
CH3
CH3
3
2
1
R
Bromination of 3-acetylpyridine with Br2/HBr in glacial
acetic acid14 gave the HBr salt of bromoacetylpyridine 7.
This was converted to the amino alcohol 8 by reaction
with N-benzylaminoethanol in DMF in the presence of
K2CO3. The keto group of compound 8 was reduced
using NaBH4 in methanol to obtain the dihydroxy com-
pound 9. Treatment of compound 9 with 70% H2SO4
under reflux conditions caused dehydration15 to yield
the cyclized product 10 (see Scheme 1).
N
N
O
O
N
N
R
N
N
CH3
4
CH3
5
Figure 1. Arecoline 1 and arecoline derivatives 2–5.
The N-benzyl group was removed by refluxing amine 10
in methanol in the presence of 10% Pd–C and ammo-
nium formate16 and the resulting free amine was treated
with Boc-anhydride in THF in the presence of K2CO3 to
yield the Boc-protected compound 11. This was con-
verted to the corresponding methylamine hydroiodide
salt by reaction with methyl iodide in acetone. This on
treatment with sodium borohydride in methanol17 gave
the reduced product 12. Finally, the Boc group was re-
moved using methanolic HCl to yield the free amine 13.
R
O
R
N
NH
+
O
HO
CH2
The overall yield of morpholine 13 starting from ketone
6 (nine steps) was 36%. The secondary amine of mor-
pholine 13 can be derivatised to give the corresponding
amide, N-alkyl and/or sulphonamide derivatives by
treatment with acyl chlorides, alkyl bromides and/or
sulfonyl chlorides, respectively, and these molecules
are being evaluated as potent M1 selective muscarinic
agonists.
Figure 2. Retrosynthetic pathway for synthesizing 2-aryl substituted
morpholine.
We found that implementation of this approach was not
straightforward, particularly, for the synthesis of the 2-
pyridyl substituted morpholine 10. Since the pyridyl
group contains a nitrogen atom, epoxidation of the 3-vi-
O
O
O
N
Br
ii
i
OH
Ph
81%
88%
N
6
N
7
N
8
Ph
N
O
Ph
OH
N
iii
iv
OH
87%
85%
N
N
9
10
Boc
Boc
H
N
N
O
N
O
v
vii
91%
O
vi
92%
N
80%
N
N
CH3
CH3
11
12
13
Scheme 1. Reagents and conditions: (i) HBr, acetic acid, Br2; (ii) N-benzylaminoethanol, K2CO3, DMF; (iii) NaBH4, MeOH; (iv) 70% H2SO4, reflux;
(v) (a) 10% Pd–C, ammonium formate, MeOH reflux. (b) (Boc)2O, THF, K2CO3; (vi) (a) MeI, acetone. (b) NaBH4, MeOH; (vii) HCl, MeOH.

Y. C. Sunil Kumar et al. / Tetrahedron Letters 48 (2007) 4565–4568
4567
(220 mL) was stirred at 70 ꢁC for 5 min. Bromine (33.38 g,
0.208 mol) in 45% aq HBr (30 mL) was added dropwise,
and the reaction mixture was stirred for 3 h at the same
temperature. The reaction mixture was cooled to room
temperature and the white solid obtained was filtered and
recrystallized using methanol–hexane (1:1). Yield: 51 g,
MS (ESI) m/z 202 (M+H+).
In conclusion, we have described an efficient method for
the preparation of a 2-pyridyl substituted morpholine.
We believe that this protocol may be of value in the syn-
thesis of other pyridyl substituted morpholine analogues
as biologically active molecules. The stereospecific
reduction of the keto group18 of compound 8 to synthe-
size enantiomerically pure 2-pyridyl substituted mor-
pholines and the testing of acyl, sulfonyl and alkyl
derivatives of compound 13 for central muscarinic cho-
linergic receptor binding affinity using [3H] oxotremo-
rine-M and [3H]QNB as ligands and in a functional
assay using guinea pig ileum, are currently in progress.
15. 4-Benzyl-2-pyridin-3-yl-morpholine 10. Diol
9
(35 g,
0.128 mol) in 70% aqueous sulphuric acid (350 mL) was
heated to 100 ꢁC for 24 h. The reaction mixture was
basified using 10% aqueous sodium hydroxide and
extracted using ethyl acetate (3 · 400 mL). The combined
organic layer was washed with water followed by brine
and dried over anhydrous Na2SO4. The ethyl acetate was
removed under reduced pressure and the crude product
was purified by column chromatography (silica 60–120)
using hexane–ethyl acetate (8:2) as eluent.
Acknowledgements
Yield: 28.5 g (87%), MS (ESI) m/z 255.1 (M+H+).
1H NMR (CDCl3, 300 MHz): d 8.55 (s, 1H), 8.50 (d,
J = 4.8 Hz, 1H), 7.63 (d, J = 5.8 Hz, 1H), 7.31–7.38 (s,
5H), 7.2–7.22 (t, J = 4.2 Hz, 1H), 4.57–4.61 (dd,
J1 = 10.2 Hz, J2 = 2.1 Hz, 1H), 3.96 (d, J = 9.9 Hz 1H),
3.8–3.84 (t, J = 10.7 Hz, 1H), 3.5 (s, 2H), 2.8 (d,
J = 9.3 Hz, 1H), 2.74 (d, J = 9.3 Hz, 1H), 2.26–2.28 (t,
J = 10.7 Hz, 1H), 2.04–2.12 (t, J = 10.9 Hz, 1H). Anal.
Calcd for C16H18N2O: Calcd C, 75.56; H, 7.13; N, 11.0%.
Found C, 75.60; H, 7.10; N, 11.23%.
Y.C.S. thanks DST Project No. DV6/15/DST/2005-06,
New Delhi, for funding. This work was supported by
UGC-SAP (phase 1) Project No. DV4/375/2004-05.
K.S.R. is gratefully acknowledged to them.
Supplementary data
1H NMR and mass spectra of compounds 8–12. Supple-
mentary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.04.135.
16. N-Boc-2-pyridin-3-yl-morpholine 11. To a solution of
compound 10 (28 g, 0.11 mol) in methanol, (280 mL)
ammonium formate (34.7 g, 0.551 mol) and 10% Pd/C
(8.4 g) were added and the mixture refluxed for 5 h. The
reaction mixture was filtered through Celite and methanol
was removed under reduced pressure. The resulting deb-
enzylated compound (15 g, 0.091 mol) was dissolved in
tetrahydrofuran (150 mL), and potassium carbonate
(18.9 g, 0.1371 mol) was added followed by Boc-anhydride
(23.7 g, 0.109 mol) and the reaction stirred at 45 ꢁC for 6 h.
Tetrahydrofuran was removed under reduced pressure and
water was added and the reaction mixture was extracted
using ethyl acetate (3 · 200 mL). The combined organic
layer was dried over anhydrous sodium sulphate. Ethyl
acetate was removed under reduced pressure and the crude
product was purified by silica gel (60–120 mesh) column
chromatography using 8:2 hexane–ethyl acetate as an
eluent.
References and notes
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Pike, J. A.; Bymaster, P. F.; Sawyer, D. B.; Shannon, E.
H. J. Med. Chem. 1992, 32, 2274–2283.
Yield: 22.5 g (93%), MS (ESI) m/z 265.2 (M+H+) 1H
NMR (DMSO-d6, 400 MHz): d 8.60 (s, 1H), 8.53 (d,
J = 4.8 Hz, 1H), 7.78 (d, J = 7.2 Hz, 1H), 7.38–7.40 (t,
J = 4.0 Hz, 1H), 4.47–4.50 (dd, J1 = 12.0 Hz, J2 = 4.0 Hz,
1H), 3.94–3.97 (m, 2H), 3.78–3.81 (d, J = 12.0 Hz, 1H),
3.5–3.56 (t, J = 12.0 Hz, 1H), 3.0–3.1 (br m, 1H), 2.8–2.9
(br m, 1H), 1.4 (s, 9H), Anal. Calcd for C14H20N2O3: Calcd
C, 63.6; H, 7.63; N, 10.6%. Found C, 63.56; H, 7.69; N,
10.58%.
N-Boc-2-(pyridin-3-yl) morpholine methyl iodide salt. To a
solution of compound 11 (20 g, 0.075 mol) in acetone
(200 mL), methyl iodide (32 g, 0.227 mol) was added at
0 ꢁC and the mixture was stirred at 0 ꢁC for 4 h and then at
25 ꢁC for 8 h. The yellow solid formed was filtered and
washed using cold acetone.
7. Christie, J. E.; Shering, A.; Ferguson, J.; Glen, A. I. M.
Br. J. Psychiat. 1981, 138, 46–50.
8. Saunders, J.; Cassidy, M.; Freedman, S. B.; Harley, E. A.;
Iversen, L. L.; Kneen, C.; MacLeod, A. M.; Merchant, K.;
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M. J.,; Honore, T. J. Med. Chem. 1991, 34, 687–692.
10. Wijtmass, R.; Vink, K. S. M.; Schoemaker, E. H.;
VanDelft, F. L.; Blaauw, R. H.; Rutjes, P. J. T. Synthesis
2004, 5, 641–662.
Yield: 30.0 g (97%), MS (ESI) m/z 407.32 (M+H+), Mole-
cular formula: C15H23IN2O3, 1H NMR (CDCl3, 300 MHz):
d 9.37 (d, J = 6.0 Hz, 1H), 9.08 (s, 1H), 8.41 (d, J = 7.8 Hz,
1H), 8.13–8.17 (t, J = 6.9 Hz, 1H), 4.64–4.75 (br m, 4H),
4.2–4.2 (d, J = 12.9 Hz, 1H), 4.03–4.07 (d, J = 11.4 Hz
1H), 3.96 (br m, 1H), 3.67–3.75 (t, J = 11.85 Hz, 1H), 3.09
(br m, 1H), 2.91–2.99 (t, J = 11.85 Hz, 1H), 1.43 (s, 9H).
17. N-Boc-2-(1-Methyl-1,2,5,6-tetrahydropyridin-3-yl)-morphol-
ine 12. To a solution of methyl iodide salt 11 (30 g,
11. (a) Bouron, E.; Goussard, G.; Marchand, C.; Bonin, B.;
Pannecoucke, X.; Quirion, J. C.; Husson, H. P. Tetra-
hedron Lett. 1999, 40, 7227–7230; (b) Lanman, A. B.;
Myers, G. A. Org. Lett. 2004, 6, 1045–1047.
12. Brown, V. E. J. Am. Chem. Soc. 1957, 79, 3565–3566.
13. Carbin, A. R.; Dusick, E. B.; Phomphrai, K.; Fanwick, E.
P.; Rothwell, I. P. Chem. Commun. 2005, 1194–1196.
14. 2-Bromo-1-pyridin-3-yl ethanone 7. A solution of 3-acetyl-
pyridine (25 g, 0.206 mol), in 33% HBr in acetic acid

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Y. C. Sunil Kumar et al. / Tetrahedron Letters 48 (2007) 4565–4568
0.0738 mol) in methanol (300 mL) at 0 ꢁC, sodium boro-
Yield: 17.0 g (81%), MS (ESI) m/z 283.32 (M+H+),
1H NMR (CDCl3, 300 MHz): d 5.77 (br s, 1H), 3.71–
3.86 (br m, 3H), 3.46–3.50 (m, 1H), 2.89–2.91 (br, 3H),
2.76 (br, 2H), 2.43–2.52 (br m, 2H), 2.22 (s, 3H), 2.02–2.2
(br, 2H), 1.44 (s, 9H). Anal. Calcd for C15H26N2O3: Calcd
C, 63.8; H, 9.28; N, 9.92%. Found C, 63.82; H, 9.30; N,
9.89%.
hydride (7.03 g, 0.185 mol) was added portionwise and the
mixture stirred at 30 ꢁC for 8 h. Methanol was removed
under reduced pressure, water was added and the mixture
extracted using ethyl acetate (3 · 300 mL). The combined
organic layer was dried over anhydrous sodium sulphate
and purified through silica gel (60–120 mesh) column
chromatography using 7:3 hexane–ethyl acetate as an
eluent.
18. Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40,
40–73.