Synthesis of furanyl and oxazolyl N-substituted piperidine and imidazoline salts as potential agonists of M1 muscarinic receptors

Article abstract of DOI:10.1002/jhet.5570440644

(Chemical Equation Presented) Furanyl and oxazolyl N-substituted imidazoline salts were prepared by reacting furanyl and oxazolyl esters with ethylenediamine and trimethyl aluminum, followed by the addition of methyl iodide or hydrogen chloride. The piperidinium salts were prepared by treating furanyl and oxazolyl chlorides with piperidine base, followed by the addition of methyl iodide or hydrogen chloride.

Full text of DOI:10.1002/jhet.5570440644

Nov-Dec 2007
1517
Synthesis of Furanyl and Oxazolyl N-substituted
Piperidine and Imidazoline Salts as Potential Agonists
of M1 Muscarinic Receptors
Andreina Aguado, John Boulos*, Anladys Carreras, Angelica Montoya,
and Judith Rodriquez
Department of Physical Sciences, Barry University, Miami Shores, Florida 33161 USA
Received December 27, 2006
R2
R2
X
X
N
OR3
R1
O
R1
O
O
N
CH3
R1 = H, Me; R2 = H, Me; R3 = Me, Et; X = C, N
Furanyl and oxazolyl N-substituted imidazoline salts were prepared by reacting furanyl and oxazolyl
esters with ethylenediamine and trimethyl aluminum, followed by the addition of methyl iodide or
hydrogen chloride. The piperidinium salts were prepared by treating furanyl and oxazolyl chlorides with
piperidine base, followed by the addition of methyl iodide or hydrogen chloride.
J. Heterocyclic Chem., 44, 1517 (2007).
on CHO cell lines expressing muscarinic receptors. These
quaternary salts can also be used pharmacologically as
gastroprokinetic agents to increase gastrointestinal
motility.
INTRODUCTION
Potential M1 muscarinic agonists have been synthesized
in our laboratory based on Schulman’s model of the
muscarinic pharmacophore. Schulman’s model [1] is
based on detailed conformational analyses of known
muscarinic agonists. Muscarinic agonists are currently
therapeutic targets for the symptomatic treatment of
Alzheimer’s disease. The cholinergic hypothesis
advanced by Schulman is based on the fact that, while
neurons which express the M2 muscarinic receptors are at
risk of degenerating, the cortical neurons expressing the
M1 subtype which synapse with them are not altered.
These M1 receptors can become activated by selective
agonists that could alleviate the symptom of Alzheimer’s
disease. Potent agonists should mimic the effects of
acetylcholine in the brain by binding to the receptor site
through a cationic head group, preferably a quaternary
ammonium group. A second binding site on these agonists
will make use of a region of negative electrostatic
potential, preferably an ester or ether group, that can
interact with a positive receptor residue through hydrogen
bonding. Several pharmacological attributes for
muscarinic activity are highly desirable for those potential
agonists. Selective agonists can reduce side effects by
having little effect on muscarinic M2 receptors in cardiac
and smooth muscles. These agonists must be able to
penetrate the blood-brain barrier in order to reach the
cortical neurons. Tertiary amines are reasonable
candidates since they can be protonated and depronated at
physiological pH and may cross the blood- brain barrier in
their neutral forms. Tertiary amines are for in vivo testing
while quaternary ammonium salts are for in vitro testing
Over the last few years, many compounds [2] that
conformed to Schulman’s model were synthesized in our
laboratory and tested for muscarinic activity.
Unfortunately, biological test results from MDS Pharma
services had revealed no significant muscarinic receptor
affinity. However, recent work by Scapecchi [3] had
shown that a compound with similar attributes could
functionally be a M2 partial agonist. In light of this new
development, we decided to synthesize novel compounds
containing piperidine and imidazoline moieties. Those
compounds were tested and, again, no significant affinity
was observed. The synthesis of these compounds is the
main focus of this paper.
Furanyl N-substituted piperidine salts 5 and 6
(Scheme 1) were synthesize by reducing furfural 1 with
sodium borohydride in basic solution to form the
corresponding alcohol 2. The alcohol was converted to
furanyl chloride 3 with triphenyl phosphine in carbon
tetrachloride. The chloride was then coupled with
piperidine, through nucleophilic substitution, to form
furanyl N-substituted piperidine base 4. Methyl iodide or
hydrogen chloride was added to the base to form the
corresponding methyl iodide and hydrochloride salts 5
and 6, respectively.
Oxazolyl N-substituted piperidine salts (Scheme 2)
were prepared by reducing oxazolyl esters with lithium
aluminum hydride (LAH) in anhydrous ether to yield
alcohol 10. The alcohol was then converted to oxazolyl

1518
A. Aguado, J. Boulos, A. Carreras, A. Montoya, and J. Rodriquez
Vol 44
corresponding oxazolyl N-substituted imidazoline base
Scheme 1
16. The base was then converted to the methyl iodide salt
17.
OH
H
H
O
2
Scheme 3
Ph3P/ CCl4
CH3
O
O
O
O
SO2Cl2
HCONH2
HCOOH
N
Cl
OEt
O
OEt
OEt
O
3
Cl
15
O
Piperidine
H2N
Al(Me)3
N
H2N
CH3
H
H
CH3
O
N
O
4
CH3
N
CH3I
H
+
HCl
MeI
N
N
I-
O
N
N
16
17
H
+
+
Me
N
N
Cl -
H
O
H
O
I -
6
The furanyl N-substituted imidazoline methyl iodide
salt 21 (Scheme 4) was synthesized by converting furfural
18 to its corresponding methyl ester 19 with a mixture of
manganese dioxide, sodium cyanide and methanol [5].
The ester was then treated with ethylene diamine and
trimethyl aluminum in toluene to produce the base 20.
The base was converted to the methyl iodide salt 21.
5
chloride 11 with triphenyl phosphine in carbon
tetrachloride. Piperidine was added to the chloride to yield
oxazolyl N-substituted piperidine base 12. The hydro-
chloride and methyl iodide salts were made from the base
13 and 14, respectively.
The oxazolyl N-substituted imidazoline salt (Scheme 3)
was prepared by first condensing ethyl chloro acetoacetate
8 with formamide in acid solution to produce the oxazolyl
ester 15. The ester was then reacted with ethylene diamine
and trimethyl aluminum in toluene [4] to form the
Scheme 4
MnO2/NaCN
MeOH
H
OCH3
H
O
H
O
O
O
19
18
Al(Me)3
Scheme 2
H2N
NH2
Cl
CH3
MeI
N
OEt
N
OEt
N
SO2Cl2
CH3COOH
CH3CONH2
H
H
O
O
OEt
+
H3C
HN
H3C
O
HN
O
O
I -
O
O
9
O
LiAlH4
CH3
8
7
20
21
CH3
Cl
Ph3P/CCl4
EXPERIMENTAL
N
N
OH
H3C
H3C
O
O
Reagents were purchased from Aldrich Chemical Company
(St. Louis, MO) unless otherwise noted, and all starting liquid
materials were distilled before use. NMR spectra were recorded
on a Varian 300 MHz spectrometer. IR spectra were recorded on
a Nicolet Impact 400D FT-IR and mass spectra on a Hewlett
Packard 5972 Series MS interfaced with a Hewlett Packard 5890
Series II Plus GC. Elemental analyses were carried out by
Galbraith Laboratories (Knoxville, TN) and all biological assays
were conducted at MDS Pharma services (Taiwan). Melting
points were determined on a MEL-TEMP II purchased from
Laboratory Devices and are uncorrected.
11
10
Piperidine
CH3
N
CH3
N
N
HCl
+
N
Cl -
H3C
H3C
H
O
O
13
12
CH3I
CH3
N
Furfuryl chloride (3). A mixture of carbon tetrachloride (90
ml), furfuryl alcohol 2 (9.8 g, 0.100 mole) and triphenyl
phosphine (34.09 g, 0.130 mole) was refluxed for one hour. The
mixture was allowed to cool to room temperature, and 100 ml of
+
N
I -
H3C
CH3
O
14

Nov-Dec 2007
Synthesis of Furanyl and Oxazolyl N-Substituted Piperidine and Imidazoline Salts
1519
anhydrous pentane was added with stirring. The solution was
filtered, and the precipitate washed a few times with a total of 50
ml of anhydrous pentane. The combined filtrate was then
concentrated and distilled at 28-30º/4-5 mmHg to yield 6.65 g
of liquid furfuryl chloride 3 (43.5%). H nmr (CDCl3): ꢀ 4.9 (s,
2H), 6.6 (m, 2H), 7.7 (d, 1H).
3H), 2.5 (s,3H), 4.3-4.7 (q, 2H), 8.0 (s, 1H); ir (CCl4): 1720
(C=O), 1610, 1560, 1440 cm-1.
(2,4-Dimethyloxazol-5-yl)methanol (10). To 50 mL of
anhydrous ether at -10 °C under nitrogen were added
simultaneously, with mechanical stirring, a solution of the ester
9 (13.0 g, 70 mmol) in 15 mL of anhydrous ether and a solution
of LAH (3.47 g, 90 mmol) in 56 mL of anhydrous ether. After
2.5 hours (including one hour for initial dropwise addition),
ethyl acetate (11 mL) was added slowly. The solution was
allowed to warm to room temperature, and excess LAH was
destroyed with 95% ethanol. The reaction mixture was
hydrolyzed with tartaric acid (19 g in water) and then made
alkaline with 6 N NaOH. The solution was saturated with
K2CO3, and the two layers were separated. The aqueous layer
was extracted with benzene, and the benzene solution was dried
over MgSO4; the ether layer was also dried over MgSO4. Both
layers were concentrated, and the residues combined and
distilled; the fraction boiling at 95 °C/ 3-4 mmHg afforded 7.3 g
of solid alcohol 10 (80%). 1H nmr (CDCl3): ꢀ 2.1 (s, 3H), 2.5 (s,
3H), 3.0-3.5 (bs, 2H), 4.6 (s, 2H); ir (CCl4): 3600-3200 (OH),
1640, 1570, 1440 cm-1. Anal. Calcd. for C6H9NO2: C, 56.68; H,
7.13; N, 11.02. Found: C, 56.75; H, 6.98; N, 11.15.
5-Chloromethyl-2,4-dimethyloxazole (11). A mixture of the
alcohol 10 (6.0 g, 0.047 mol), anhydrous carbon tetrachloride
(45 mL) and triphenyl phosphine (17.04 g, 0.065 mol) was
refluxed for 2 hours. The reaction mixture was allowed to cool
to room temperature and then diluted with 100 mL of dry
pentane. The mixture was filtered and the filtrate concentrated to
one-fourth of its original volume. The concentrated product was
distilled to yield 3.73 g of the liquid chloride 11 (54.6%) which
was collected at 53-54 °C/2-3 mmHg. 1H nmr (CDCl3): ꢀ 2.1 (s,
3H), 2.4 (s, 3H), 4.5 (s, 2H).
1
1-(2-Furylmethyl)piperidine (4). A solution of 3.3 g of 3
(0.0283 mol) in acetonitrile was added to a mixture containing
2.4 g of piperidine (0.0283 mol), 2.0 g of anhydrous sodium
carbonate and 15 ml of acetonitrile. After addition, the mixture
was allowed to stir overnight, filtered, and concentrated to yield
1
4.3 g of fairly pasty and pure 4 (92%). H nmr (CDCl3): ꢀ 1.4
(m, 2H), 1.6 (m, 4H), 2.4 (m, 4H), 3.5 (s, 2H), 6.2 (d, 1H), 6.3
(dd, 1H), 7.4 (d, 1H). MS: m/z 165 (M+), 81 (base), 53.
1-(2-Furylmethyl)-1-methylpiperidinium iodide (5). To a
solution containing 2.0 g (0.012 mol) of 4 dissolved in 10 ml of
CH2Cl2 was added 2.0 g of methyl iodide (0.014 mol) with
stirring. The solution was stirred overnight, and concentrated to
yield 3.5 g of solid 5 (94%), m.p 163-165 °C. 1H nmr (CDCl3): ꢀ
1.8 (m, 2H), 2.2 (m, 4H), 3.4 (s, 3H), 3.8 (m, 4H), 5.2 (s, 2H),
6.5 (d, 1H), 7.1 (dd, 1H), 7.6 (d, 1H). Anal. Calcd. For
C11H18NOI: C 43.01 %, H 5.91 %, N 4.56 %, I 41.31 %. Found:
C 43.31 %, H 5.95 %, N 4.57 %, I 43.36 %
1-(2-Furylmethyl)piperidinium chloride (6). Hydrogen
chloride gas was passed through a solution containing 2.0 g
(0.012 mol) of 4 dissolved in 10 ml of CH2Cl2 for about ten
minutes. The solution was stirred overnight, and concentrated to
1
yield 2.3 g of solid 6 (96%), m.p 105-107 °C. H nmr (D2O): ꢀ
1.4-2.2 (m, 6H), 2.8-3.8 (m, 4H), 5.0 (s, 2H), 6.5 (d, 1H), 6.7
(dd, 1H), 7.6 (d, 1H). Anal. Calcd. C10H16NOCl: C 59.55 %, H
7.99 %, N 6.95 %, Cl 17.58%. Found: C 58.65 %, H 7.94 %, N
6.95 %, Cl 17.32 %.
Ethyl chloroacetoacetate [6] (8). Ethyl acetoacetate 7 (130 g,
1 mol) was placed in a 500 mL 3-necked flask fitted with a
dropping funnel, mechanical stirrer and a gas-absorption trap.
Sulfuryl chloride (135 g, 1 mol) was then added dropwise with
external cooling (ice-bath) for 2 hours. The solution was allowed
to stand overnight and the remaining SO2 and HCl were
removed by evaporation. The resulting solution was then
distilled using a Vigreux column at 25 mmHg, and the fraction
boiling between 95-100 °C was collected to afford 95 g of liquid
ethyl chloroacetoacetate 8 (64%); literature values: bp 85-89
1-[(2,4-Dimethyloxazol-5-yl)methyl]piperidine (12). 3.39 g
of 11 (0.0235 mol) in acetonitrile was added slowly to a mixture
containing 2.0 g of piperidine (0.0235 mol), 2.0 g of anhydrous
sodium carbonate and 15 ml of acetonitrile. After addition, the
mixture was allowed to stir overnight, filtered, concentrated to
yield 3.66 g of fairly pasty and pure 12 (80%). 1H nmr (CDCl3):
ꢀ 1.35-1.68 (m, 6H), 2.05 (s, 3H), 2.35 (s, 3H), 3.0-3.2 (m, 4H),
3.38 (s, 2H). MS: m/z 194 (M+), 110 (base) 84, 42.
1-[(2,4-Dimethyloxazol-5-yl)methyl]piperidinium chloride
(13). Hydrogen chloride gas was bubbled through a solution
containing 1.12 g of 12 (0.00577 mol) and 10 mL of dichlo-
methane for about 10 minutes. The solution was concentrated
and the residue recrystallized from acetonitrile to yield 1.05 g of
1
°C/17 mmHg, (93-97%). H nmr (CDCl3): ꢀ 1.1-1.5 (t, 3H), 2.4
(s, 3H), 4.1-4.5 (q, 2H), 4.8 (s, 1H).
Ethyl-2,4-dimethyl-1,3-oxazole-5-carboxylate (9).
A
1
mixture of ethyl chloroacetoacetate 8 (66.1 g, 0.40 mol),
acetamide (47.4g, 0.80 mol) and glacial acetic acid (146 g) was
refluxed for 22 hours. The residual dark solution was cooled in
an ice-bath and made alkaline with 6 N sodium hydroxide. The
mixture was extracted with ether and the combined extracts were
dried over sodium sulfate. After filtration, the ether was
removed and the remaining black residue (60 g) was distilled
under reduced pressure to give 37.6 g of a colorless liquid. The
distillate was shaken with 50 mL of cold 50% concentrated
sulfuric acid. Two layers were formed, the upper one unreacted
ethyl chloroacetoacetate and the lower sulfuric acid containing
the oxazole. The sulfuric acid layer was diluted with cold water
and made alkaline with 6 N KOH. The solution was then
extracted with ether, and the combined ether extracts were dried
over magnesium sulfate. The solution was concentrated and the
residue distilled between 60-62 °C/4-5 mmHg to afford 30 g of
the solid ester 9 (25%). 1H nmr (CDCl3): ꢀ 1.2-1.6 (t, 3H), 2.4 (s,
solid 13 (79%), mp 226-227 °C. H nmr (CDCl3): ꢀ 1.2-1.8 (m,
6H), 2.0 (s, 3H), 2.3 (s, 3H), 2.6-3.0 (m, 2H), 3.2-3.5 (m, 2H),
4.2 (s, 2H). Anal. Calcd. For C11H19N2OCl: C 57.26 %, H 8.30
%, N 12.14 %, Cl 15.37 %. Found: C 57.26 %, H 8.40 %, N
12.20 %, Cl 15.00 %.
1-[(2,4-Dimethyloxazol-5-yl)methyl]-1-methyl piperidinium
iodide (14). Excess methyl iodide was added to 0.5 g (0.00258
mol) of 12 dissolved in 10 mL of acetonitrile. The reaction
mixture was stirred overnight, concentrated and the residue
recrystallized from tert-butyl alcohol/methanol to yield 0.52 g
(60%) of solid 14, mp 163 -164 °C. 1H nmr (D2O): ꢀ 1.4-1.8 (m,
6H), 2.0 (s, 3H), 2.4 (s, 3H), 3.0-3.4 (m, 4H), 3.6 (m, 3H), 4.6 (s,
2H). Anal. Calcd. For C12H21N2OI: C 42.87 %, H 6.295 %, N
8.332 %, I 37.74 %. Found: C 42.28 %, H 6.50 %, N 8.13 %, I
37.30 %.
5-(4,5-Dihydro-1H-imidazol-2-yl)-4-methyloxazole [4] (16).
To a solution of ethylene diamine (0.0557 mol) in 65 mL of

1520
A. Aguado, J. Boulos, A. Carreras, A. Montoya, and J. Rodriquez
Vol 44
toluene was added dropwise, with cooling, a 2 M solution of
Al(CH3)3 (0.0557 mol) in toluene. A solution of 5.00 grams of
ester 15 (0.032 mol) in 20 mL of toluene was added at 0 °C, and
the mixture was refluxed for 15 hours. The mixture was
concentrated to leave a residue. Water was added and the residue
was extracted with dichloromethane. The combined organic
extracts were dried over MgSO4, filtered and concentrated.
Column chromatography over silica gel with 10:1 CH2Cl2/
of toluene was added at 0 °C, and the mixture was refluxed for
10 hours. The mixture was concentrated to leave a pasty residue.
Water was added and the residue was extracted with dichloro-
methane. The organic layers were dried over MgSO4 and
evaporated. Column chromatography over silica gel with 10:1
CH2Cl2/MeOH afforded 0.75 g (54%) of a pasty compound 20.
1H nmr (CDCl3) 3.8 (m, 2H), 4.1 (m, 2H), 6.6 (m, 1H), 7.2 (d,
1H), 7.7 (d, 1H). MS: m/z 136 (M+), 107, 79, 32.
2-(2-Furyl)-1-methyl-4,5-dihydro-1H-imidazole hydro-
iodide (21). To 0.50 g (0.0037 mol) of the base 20 was added
0.70 g (0.005 mol) of CH3I. The mixture was stirred overnight at
room temperature. The residue was dried under vacuum and re-
crystallized from acetonitrile to afford 0.75 g of the salt 21
(73%). Anal. Calcd. For C8H11N2OI: C 34.54 %, H 4.0 %, N
10.08 %, I 45.63 %. Found: C 34.20 %, H 3.91%, N 10.06 %, I
46.00 %.
1
MeOH afforded solid 16, 1.9 g (39.6 %), m.p. 105-108 °C. H
nmr (CDCl3): ꢀ 2.5 (s, 3H), 3.5 (m, 2H), 4.0 (m, 2H), 5.0 (s,
1H), 7.8 (s, 1H). MS: m/z 151 (M+), 122, 95, 82, 53.
4-Methyl-5-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)
oxazole hydroiodide (17). To 1.0 g (0.0066 mol) of the base 16
was added 0.95 g (0.0067 mol) of CH3I. The mixture was stirred
overnight at room temperature. The residue was dried under
vacuum and re-crystallized from acetonitrile to afford 1.25 g of
1
the salt 17 (65%), mp 209-210 °C. H NMR (D2O): ꢀ 2.2 (s,
Acknowledgement. We thank the MARC program and the
Department of ]Physical Sciences at Barry University for their
support.
1
3H), 3.9 (s, 3H), 8.25 (s, 1H). H nmr (CD3OD): ꢀ 2.2 (s, 3H),
4.2 (s, 3H), 5.0 (m, 4H), 8.6 (s, 1H). Anal. Calcd. For
C8H12N3OI: C 32.78 %, H 4.126 %, N 14.34 %, I 43.29 %.
Found: C 31.00 %, H 3.71%, N 14.70 %, I 46.10 %.
REFERENCES AND NOTES
Methyl-2-furoate [5] (19). To a mixture containing 7.35 g
NaCN (0.15 mol), 13.05 g of activated MnO2, 10 mL of glacial
acetic acid and 25 mL of anhydrous methanol was added 10.8 g
of furfural (0.11 mol). The reaction mixture was allowed to stir
overnight and gravity filtered to remove the manganese oxide.
The filtrate was concentrated and chromatographed on silica gel
(70-270 mesh) using a 1:1 mixture of hexane/dichloromethane
to yield 4.0 g of solid 19 (28.9%), Rf (hexane/dichloromethane)
0.34. H nmr (CDCl3): ꢀ 3.9 (s, 3H), 6.5 (dd, 1H), 7.2 (d, 1H),
7.6 (d, 1H).
2-(2-Furyl)-4,5-dihydro-1H-imidazole (20). To a solution of
ethylene diamine (0.019 mol) in 20 mL of toluene was added
dropwise, with cooling, a 2 M solution of Al(CH3)3 (0.019 mol)
in toluene. A solution of 1.3 g of ester 19 (0.0103 mol) in 7 mL
[1] Schulman, J.; Sabio, M. J. Med. Chem., 1983, 26, 817.
[2a] Boulos, J.; Schulman, J. J. Heterocycl. Chem., 1998 35, 859;
[b] Boulos, J.; Stujenske, C. J. Heterocycl. Chem., 2006, 43, 443.
[3] Scapecchi, S.; Matucci, R.; Bellucci, C.; Buccioni, M.;
Guandalini, L.; Martelli, C.; Manettti, D.; Martini, E.; Marucci, G.;
Nesi, M.; Romanelli, M.; Teodori, E.; Gualtieri, F. J. Med. Chem., 2006,
49(6), 1925.
[4] Touzeau, F.; Arrault, A.; Guillaumet, G.; Scalbert, E.;
Pfeiffer, B.; Rettori, M.; Renard, P.; Merour, J. J. Med. Chem., 2003,
46(10), 1962.
1
[5] Corey, J.; Gilman, N.; Ganem, B. J. Am. Chem. Soc.,
1968, 90(20), 5616.
[6] Dornow, A.; Hell, H. Chem. Ber., 1961, 94, 1248.