Synthesis of 1,2,5,6-/1,2,3,6-Tetrahydropyridinyl-tetrahydrocyclopentaisoxazole Derivatives

Article abstract of DOI:10.1002/jhet.5570400602

Fused tetrahydrocyclopenta-isoxazoles were synthesized by 1,3-dipolar cycloaddition reactions with pyridinealdoxime or tetrahydropyridinealdoxime and cycloalkenes.

Full text of DOI:10.1002/jhet.5570400602

Nov-Dec 2003
957
Synthesis of 1,2,5,6-/1,2,3,6-Tetrahydropyridinyl-tetrahydro-
cyclopentaisoxazole Derivatives
Mija Ahn, Jung Mee Park, Ihl-Young Choi Lee, and Myung Hee Jung*
Korea Research Institute of Chemical Technology, P.O.Box 107, Yusong, Taejon 305-600, Korea
Received April 11, 2003
Fused tetrahydrocyclopenta-isoxazoles were synthesized by 1,3-dipolar cycloaddition reactions with
pyridinealdoxime or tetrahydropyridinealdoxime and cycloalkenes.
J. Heterocyclic Chem., 40, 957 (2003).
Recent research effort on Alzheimer's Disease (AD) has
focused on the development of muscarinic M agonists [1].
1
M agonists are expected to bind selectivity to M mus-
1
1
carinic receptors and stimulate phosphoinositide (PI)
turnover in the hippocamus [2]. Arecoline (I, Figure 1), a
naturally occurring alkaloid, is one of the first clinical
drugs used for AD [3]. Despite being an M agonist, how-
1
ever, its lack of subtype selectivity and poor metabolic sta-
bility caused by the ester moiety, has hindered its use as a
therapeutic agent.
Figure 1. Muscanimic agonists
To improve the duration of action and pharmacological
profile (potency and efficacy), the ester moiety had to be
replaced. Continuing efforts to synthesize derivatives of
this lead compound have brought about xanomeline (II)
[4] and milameline (III) [5]. Chemically, they possess a
1,2,5,6-tetrahydropyridine ring while the unstable ester
moiety of arecoline has been replaced with its bioisosteres
alkoxythiadiazole and alkoxyimino groups, respectively.
The structure of xanomeline (II) shows a resemblance to
that of tetrahydropyridinylbenzoxazoles (IV) [6] and
tetrahydropyrimidinylbenzoxazoles (V) [7] previously
prepared in our laboratory (Figure 2). Compounds IV and
V, which possess a benzoxazole ring, exhibited interesting
biological activity as potential agrochemicals as well as
clinical drugs. SAR studies have revealed that pharmaco-
logical activity may be maintained if the ester in arecoline
is exchanged with a heterocyclic ring. Therefore, a series
of tetrahydrocyclopenta-isoxazole system as an ester
bioisostere seemed like an attractive target.
Figure 2. Structures of tetrahydropyridinylbenzoxazoles (IV) and tetrahy-
dropyrimidinylbenzoxazoles (V).
Scheme 1
The isoxazoles belong to an important structural group
found in a variety of anticonvulsants [8], antivirals [9], and
analgesics [10]. Many papers have been published describ-
ing the synthesis of isoxazole derivatives [11]. In our con-
tinuous research program on the synthesis of isoxazole
derivatives as possible M agonists, we describe in this
1
report the synthesis of 1-methyl-1,2,5,6-tetrahydropyridin-
3-yl-tetrahydrocyclopenta/furoisoxazoles 5a-c and
1-methyl-1,2,3,6-tetrahydropyridin-4-yl-tetrahydrocyclo-
penta/furoisoxazoles 8a-c as shown is Schemes 1 and 2.
The starting material 3-pyridinealdoxime 1 was pre-
pared from 3-pyridinealdehyde and hydroxylamine
hydrochloride according to a known procedure [12].
Treatment of`3-pyridinealdoxime 1 and cycloalkenes 2
with sodium hypochlorite in dichloromethane solution at 0
°C gave the bicyclic compounds 3a-c in moderate to good
yields by 1,3-dipolar cycloaddition reaction. The expected
cis-ring junction stereochemistry of 3a-c was confirmed

958
M. Ahn, J. M. Park, I.-Y. Choi Lee, and M. H. Jung
Vol. 40
by X-ray crystallography [13] and result of 3b is shown in
Figure 3. Compounds 3a-c were further treated with the
conventional method of methyl iodide in acetone to afford
1-methylpyridinium iodides 4a-c in good yields.
pound 7 and the corresponding cycloalkenes 2 by 1,3-
dipolar cycloaddition. Better purity was obtained for com-
pounds 8a-c when prepared as tosylate salts instead of the
oxalate salts.
Treatment of 1-methylpyridinium salts 4a-c with
sodium borohydride in cold (-20 °C) methanol yielded
tetrahydropyridinyl-cyclopenta/furoisoxazole derivatives
as the sole product. For enhanced purity and stability, the
obtained derivatives were further treated with oxalic acid
to afford the oxalate salts 5a-c.
EXPERIMENTAL
Melting points were determined on a Thomas-Hoover appara-
tus and are uncorrected. Infrared spectra were recorded on a
Mattson Genesis II FTIR. Nuclear magnetic resonance spectra
were measured on a Brucker AM-300 spectrometer. For single
crystal X-ray diffractometry, the intensity data were collected at
room temperature on a Siemens P4 four-circle X-ray diffrac-
tometer with graphite-monochromated Mo Kα radiation (λ =
0.71073 Å). All calculation in the structural solution and refine-
ment was performed using the Siemens SHELXTL crystallo-
graphic software package on a Silicon Graphics system. All the
non-hydrogen atoms were refined anisotropically; all the hydro-
gen atoms fixed at the calculated positions with the isotropic
thermal parameters were included in the final structure factor cal-
culations.
General Procedure for Preparation of 3-Pyridin-3-yl-tetrahydro-
cyclopenta/furoisoxazoles (3a-c).
Figure 3. X-Ray Crystallography of 3b (arbitrary numbering system).
To a stirred solution of pyridine-3-carboxaldehyde oxime 1
(10.0 mmol) in dichloromethane (100 ml) was added cycloalkene
2 (5.0 mmol). The mixture was stirred at 0 °C, after NaOCl
(20.50 mmol) was added over a 30 min. period. After 4 h stirring
at room temperature, the organic layer was separated, and the
aqueous layer was extracted with dichloromethane, combined to
Compounds 8a-c were synthesized as positional isomers
of compounds 5a-c for a structure-activity relationship
study. Synthesis of compounds 8a-c is shown in Scheme 2.
Similar to the previous experiment, starting from
4-pyridinealdehyde 6, we obtained 4-pyridinealdoxime
[12]. Before the cycloaddition reaction, methylation of
4-pyridinealdoxime led to the corresponding pyridinium
salts which underwent hydride reduction with sodium
borohydride to produce compound 7 as starting material.
The bicyclic tosylate salts 8a-c were prepared from com-
the organic layer, dried over anhydrous MgSO , and then evapo-
4
rated in vacuo. The residue was purified by column chromatogra-
phy on silica gel (n-hexane:acetone=2:1) to give the title com-
pounds 3a-c.
3-Pyridin-3-yl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole
(3a).
This compound was obtained as yellow oil, yield 58 %, ir
Scheme 2
-1
1
(neat): 3030 (CH), 1590 cm ; H nmr (CDCl ): δ 8.84 (dd, 1H,
3
C2'-H), 8.59 (dd, 1H, C6'-H), 8.05 (dt, 1H, C4'-H), 7.31 (ddd,
1H, C5'-H), 5.25 (dd, 1H, C6a-H), 4.04 (m, 1H, C3a-H), 2.17,
1.77 (m, 2H, C5-H), 1.89 (m, 2H, C4-H), 1.75, 1.53 (m, 2H, C6-
13
H); C nmr (CDCl ): δ 156.1 (C-3), 150.4 (C-6'), 147.8 (C-2'),
3
133.9 (C-4'), 125.5 (C-3'), 123.5 (C-5'), 88.1 (C-6a), 51.4 (C-3a),
35.6 (C-5), 31.3 (C-4), 23.3 (C-6)
Anal. Calcd. for C H N O•HCl: C, 58.80; H, 5.83; N, 12.47.
11 12
2
Found: C, 58.92; H, 5.85; N, 12.43.
3-Pyridin-3-yl-3a,4,5,6a-tetrahydrofuro[3,2-d]isoxazole (3b).
This compound was obtained as white powder, yield 35 %, mp
-1
1
82-83°; ir (potassium bromide): 3050 (CH), 1595, 1090 cm ; H
nmr (CDCl ): δ 8.83 (d, 1H, C2'-H), 8.62 (dd, 1H, C6'-H), 8.05
3
(dt, 1H, C4'-H), 7.34 (dd, 1H, C5'-H), 6.33 (d, 1H, C6a-H), 4.17
(dd, 1H, C3a-H), 4.07, 3.58 (m, 2H, C5-H), 2.27, 2.09 (m, 2H,
13
C4-H); C nmr (CDCl ): δ 155.2 (C-3), 151.2 (C-6'), 147.8 (C-
3
2'), 134.0 (C-4'), 124.8 (C-3'), 123.8 (C-5'), 109.5 (C-6a), 66.5
(C-5), 50.9 (C-3a), 30.2 (C-4). Crystal data for compound 3b are
found in Table.
Anal. Calcd. for C
H N O : C, 63.15; H, 5.30; N, 14.73.
10 10 2 2
Found: C, 63.52; H, 5.49; N, 14.92.

Nov-Dec 2003
1,2,5,6-/1,2,3,6-Tetrahydropyridinyl-tetrahydrocyclopentaisoxazole Derivatives
959
3-Pyridin-3-yl-3a,4,6,6a-tetrahydrofuro[3,4-d]isoxazole (3c).
General Procedure for Preparation of 1-Methyl-1,2,5,6-tetrahy-
dropyridin-3-yl-tetrahydrocyclopenta/furoisoxazole Oxalates
(5a-c).
This compound was obtained as white crystal, yield 20 %,
mp 113-114°; ir (potassium bromide): 3060 (CH), 1588, 1090
-1
1
cm ; H nmr (CDCl ): δ 8.75 (dd, 1H, C2'-H), 8.61 (dd, 1H,
To a cooled (-20 °C) and stirred suspension of 4a-c (4.0 mmol)
in methanol (40 ml) was added portion-wise sodium borohydride
(4.5 mmol). After stirring for 5 h at room temperature, the solvent
was evaporated. The residue was dissolved in ethyl acetate and
3
C6'-H), 8.02 (dt, 1H, C4'-H), 7.32 (2xdd, 1H, C5'-H), 5.39 (dd,
1H, C6a-H), 4.30 (d, 1H, C6-H), 4.26 (m, 1H, C3a-H), 4.10 (d,
13
1H, C4-H), 3.84 (dd, 1H, C4-H), 3.74 (dd, 1H, C6-H); C nmr
(CDCl ): δ 154.2 (C-3), 151.0 (C-6'), 147.6 (C-2'), 134.0
washed with aqueous NaHCO solution. The organic layer was
3
3
(C-4'), 124.8 (C-3'), 123.8 (C-5'), 86.6 (C-6a), 76.2 (C-6), 71.4
(C-4), 53.2 (C-3a).
washed with brine and dried over anhydrous MgSO . The solvent
4
was removed in vacuo and the residue was purified by flash col-
umn chromatography on silica gel (methylene chloride:
methanol) to give the reductive compounds. To a stirred solution
of above mentioned reductive compounds in 10 ml acetone was
added oxalic acid (1.0 eq). After 2 h stirring at room temperature,
the precipitates were collected by filtration and washed with a
small amount of ethyl ether, then dried under vacuum to give the
title compounds 5a-c.
Anal. Calcd. for C
H N O : C, 63.15; H, 5.30; N, 14.73.
10 10 2 2
Found: C, 62.81; H, 5.29; N, 14.71.
General Procedure for Preparation of Pyridinium Salts (4a-c).
To a stirred solution of 3a-c (5.0 mmol) in acetone (30 ml) was
added a solution of iodomethane (50.0 mmol) in acetone (10 ml).
The mixture was stirred at room temperature for 17 h. The pre-
cipitate was collected by filtration, the filter cake washed with
ethyl ether, and dried under reduced pressure to give 4a-c.
3-(1-Methyl-1,2,5,6-tetrahydropyridin-3-yl)-4,5,6,6a-tetrahydro-
3aH-cyclopenta[d]isoxazole Oxalate (5a).
3-(1-Methyl-pyridin-3-yl)-4,5,6,6a-tetrahydro-3aH-cyclopenta-
[d]isoxazole Iodide (4a).
This compound was obtained as white powder, yield 55 %, mp
138-139°; ir (potassium bromide): 3460 (COOH), 2970 (CH),
-1
1
This compound was obtained as yellow powder, yield 97 %,
1732 (CO), 1660 cm ; H nmr (DMSO-d ): δ 6.32 (m, 1H, C4'-
6
-1
1
mp 162-163°; ir (potassium bromide): 3060 (CH), 1640 cm ; H
H), 5.04 (dd, 1H, C6a-H), 4.68 (br s, COOH), 3.94-3.79 (m, 3H,
nmr (DMSO-d ): δ 9.33 (s, 1H, C2'-H), 9.01 (d, 1H, C6'-H), 8.78
C2'-H, C3a-H), 3.25 (m, 2H, C6'-H), 2.82 (s, 3H, NCH ), 2.53
6
3
(d, 1H, C4'-H), 8.18 (dd, 1H, C5'-H), 5.33 (dd, 1H, C6a-H), 4.40
(m, 2H, C5'-H), 1.90, 1.78 (m, 2H, C5-H), 1.75 (m, 2H, C4-H),
+
13
(s, 3H, N CH ), 4.27 (dt, 1H, C3a-H), 1.99, 1.74 (m, 2H, C5-H),
1.70, 1.26 (m, 2H, C6-H); C nmr (CD OD): δ 165.4 (COOH),
3
3
13
1.80 (m, 2H, C4-H), 1.68, 1.25 (m, 2H, C6-H); C nmr (DMSO-
159.3 (C-3), 129.7 (C-4'), 124.3 (C-3'), 89.8 (C-6a), 52.6, 52.4,
d ): δ 154.8 (C-3), 145.8 (C-6'), 143.7 (C-2'), 141.8 (C-4'), 129.2
51.4 (C-2', C-6', C-3a), 43.5 (NCH ), 36.8 (C-5), 33.1 (C-4),
24.7, 24.3 (C-5', C-6).
6
3
+
(C-3'), 128.0 (C-5'), 89.3 (C-6a), 50.7 (C-3a), 48.5 (N CH ), 35.4
3
(C-5), 30.9 (C-4), 23.8 (C-6).
Anal. Calcd. for C
Found: C, 56.72; H, 6.90; N, 9.38.
H N O : C, 56.75; H, 6.80; N, 9.45.
14 20 2 5
Anal. Calcd. for C
H IN O: C, 43.65; H, 4.58; N, 8.48.
12 15 2
Found: C, 43.94; H, 4.56; N, 8.55.
3-(1-Methyl-1,2,5,6-tetrahydropyridin-3-yl)-3a,4,5,6a-tetrahy-
3-(1-Methyl-pyridin-3-yl)-3a,4,5,6a-tetrahydrofuro[3,2-d]isoxa-
zole Iodide (4b).
drofuro[3,2-d]isoxazole Oxalate (5b).
This compound was obtained as white powder, yield 46 %, mp
151-152°; ir (potassium bromide): 3440 (COOH), 1757 (CO),
This compound was obtained as yellow powder, yield 97 %,
mp 205-206°; ir (potassium bromide): 3070 (CH), 1638, 1100
-1
1
1650 cm ; H nmr (CD OD): δ 6.50 (br s, 1H, C4'-H), 6.24 (d,
3
-1
1
cm ; H nmr (DMSO-d ): δ 9.39 (s, 1H, C2'-H), 9.04 (d, 1H,
1H, C6a-H), 4.05 (m, 4H, C3a-H, C5-H, C2'-H), 3.46 (m, 3H,
6
C6'-H), 8.82 (d, 1H, C4'-H), 8.21 (dd, 1H, C5'-H), 6.45 (d, 1H,
C5-H, C6'-H), 3.03 (s, 3H, NCH ), 2.75 (br s, 2H, C5'-H), 2.24
3
+
13
C6a-H), 4.52 (dt, 1H, C3a-H), 4.40 (s. 3H, N CH ), 4.05, 3.39
(m, 2H, C4-H); C nmr (CD OD): δ 166.9 (COOH), 158.4 (C-
3
3
13
(m, 2H, C5-H), 2.15 (m, 2H, C4-H); C nmr (DMSO-d ): δ
3), 131.2 (C-4'), 124.2 (C-3'), 111.2 (C-6a), 67.9 (C-5), 52.3,
6
154.4 (C-3), 146.2 (C-6'), 144.1 (C-2'), 142.2 (C-4'), 128.7 (C-3'),
128.1 (C-5'), 110.4 (C-6a), 66.6 (C-5), 50.6 (C-3a), 48.5
52.0, 51.3 (C-2', C-6', C-3a), 43.5 (NCH ), 32.0 (C-4), 24.4
(C-5').
3
+
(N CH ), 29.8 (C-4).
Anal. Calcd. for C
H N O : C, 52.34; H, 6.08; N, 9.39.
13 18 2 6
3
Anal. Calcd. for C H IN O : C, 39.78; H, 3.95; N, 8.43.
Found: C, 52.60; H, 6.16; N, 9.30.
11 13
2 2
Found: C, 40.01; H, 4.05; N, 8.63.
3-(1-Methyl-1,2,5,6-tetrahydropyridin-3-yl)-3a,4,6,6a-tetrahy-
3-(1-Methyl-pyridin-3-yl)-3a,4,6,6a-tetrahydrofuro[3,4-d]isoxa-
zole Iodide (4c).
drofuro[3,4-d]isoxazole Oxalate (5c).
This compound was obtained as white powder, yield 47 %, mp
143-144°; ir (potassium bromide): 3470 (COOH), 1726 (CO),
This compound was obtained as yellow powder, yield 96 %,
mp 179-180°; ir (potassium bromide): 3060(CH), 1636, 1070
-1
1
1630 cm ; H nmr (CD OD): δ 6.38 (br s, 1H, C4'-H), 5.32 (dd,
3
-1
1
cm ; H nmr (DMSO-d ): δ 9.35 (s, 1H, C2'-H), 9.02 (d, 1H,
1H, C6a-H), 4.24 (br t, 1H, C3a-H), 4.19 (br d, 1H, C6-H), 4.12
(br d, 1H, C4-H), 4.05 (br s, 2H, C2'-H), 3.80 (dd, 1H, C4-H),
6
C6'-H), 8.81 (d, 1H, C4'-H), 8.18 (dd, 1H, C5'-H), 5.56 (dd, 1H,
+
C6a-H), 4.58 (dt, 1H, C3a-H), 4.38 (s, 3H, N CH ), 4.15 (d, 1H,
3.72 (dd, 1H, C6-H), 3.45 (br s, 2H, C6'-H), 3.02 (s, 3H, NCH ),
3
3
13
13
C6-H), 4.07, 3.72 (2xd, 2H, C4-H), 3.68 (dd, 1H, C6-H); C nmr
2.73 (br s, 2H, C5'-H); C nmr (CD OD): δ 166.9 (COOH),
3
(DMSO-d ): δ 153.3 (C-3), 146.1 (C-6'), 143.9 (C-2'), 141.9 (C-
157.5 (C-3), 130.4 (C-4'), 124.0 (C-3'), 88.3 (C-6a), 77.4 (C-6),
6
4'), 128.7 (C-3'), 128.1 (C-5'), 88.1 (C-6a), 75.7 (C-6), 71.1 (C-
73.3 (C-4), 54.1, 52.4, 51.3 (C-2', C-6', C-3a), 43.5 (NCH ), 24.4
(C-5').
3
+
4), 52.4 (C-3a), 48.5 (N CH ).
3
Anal. Calcd. for C H IN O : C, 39.78; H, 3.95; N, 8.43.
Anal. Calcd. for C
H N O : C, 52.34; H, 6.08; N, 9.39.
13 18 2 6
11 13
2 2
Found: C, 39.85; H, 4.06; N, 8.58.
Found: C, 52.25; H, 6.13; N, 9.28.

960
M. Ahn, J. M. Park, I.-Y. Choi Lee, and M. H. Jung
Vol. 40
General Procedure for Preparation of 1-Methyl-1,2,3,6-tetrahy-
dropyridin-4-yl-tetrahydrocyclopenta/furoisoxazole Tosylates
(8a-c).
67.8 (C-5), 53.4, 51.8, 51.6 (C-2', C-6', C-3a), 43.4 (NCH ), 32.1
3
(C-4), 23.7 (C-5'), 21.6 (CH ).
3
Anal. Calcd. for C
H N O S•H O: C, 54.26; H, 6.58; N,
18 24 2 5 2
7.03; S, 8.05. Found: C, 54.64; H, 6.48; N, 7.19; S, 7.93.
Compounds 8a-c were prepared in three steps without isolation
of the pyridinium salts from 1-methyl-1,2,3,6-tetrahydropyridin-
4-aldoxime 7 according to general procedures 3a-c to 5a-c, using
p-toluene sulfonic acid instead of oxalic acid to form the salt.
3-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-3a,4,6,6a-tetra-
hydrofuro[3,4-d]-isoxazole Tosylate (8c).
This compound was obtained as white powder, yield 12 %, mp
3-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-4,5,6,6a-tetrahydro-
3aH-cyclopenta[d]isoxazole Tosylate (8a).
144-145°; ir (potassium bromide): 3470 (SO H), 3015 (CH),
3
-1
1
1220 cm ; H nmr (CD OD): δ 7.73, 7.28 (ABq, 4H, arom. H),
3
6.11 (m, 1H, C3'-H), 5.33 (dd, 1H, C6a-H), 4.21 (d, 1H, C6-H),
4.18 (br t, 1H, C3a-H), 4.08 (d, 1H, C4-H), 3.97 (br s, 2H, C2'-
H), 3.78 (dd, 1H, C4-H), 3.72 (dd, 1H, C6-H), 3.47 (br s, 2H, C6'-
This compound was obtained as white powder, yield 36 %, mp
134-135°; ir (potassium bromide): 3470 (SO H), 3040 (CH),
3
-1
1
1230 cm ; H nmr (CD OD): δ 7.73, 7.28 (ABq, 4H, arom. H),
3
H), 3.01 (s, 3H, NCH ), 2.78 (m, 2H, C5'-H), 2.41 (s, 3H CH );
3
3
6.13 (m, 1H, C3'-H), 5.15 (dd, 1H, C6a-H), 4.19, 3.70, 3.28, 2.75
(m, 6H, C2'-H, C6'-H, C5'-H), 3.88 (m, 1H, C3a-H), 3.01 (s, 3H,
13
C nmr (CD OD): δ 158.5 (C-3), 143.7, 142.2, 130.2, 127.2
3
(arom. C), 128.2 (C-4'), 124.5 (C-3'), 88.7 (C-6a), 77.5 (C-6),
73.4 (C-4), 53.9, 53.4, 51.7 (C-2', C-6', C-3a), 43.3 (NCH ), 23.9
NCH ), 2.41 (s, 3H, CH ), 2.07, 1.90 (m, 2H, C5-H), 1.85 (m,
3
3
13
3
2H, C4-H), 1.80, 1.43 (m, 2H, C6-H); C nmr (CD OD): δ
3
(C-5'), 21.6 (CH ).
3
160.3 (C-3), 143.8, 142.1, 130.2, 127.2 (arom. C), 128.4 (C-4'),
124.0 (C-3'), 90.2 (C-6a), 53.4 (C-2'), 52.2, 51.7 (C-6', C-3a),
Anal. Calcd. For C
H N O S: C, 56.82; H, 6.36; N, 7.36; S,
18 24 2 5
8.43. Found: C, 56.51; H, 6.36; N, 7.34; S, 8.38.
43.4 (NCH ), 36.8 (C-5), 33.1 (C-4), 24.7 (C-5'), 23.9 (C-6), 21.6
3
(CH ).
Anal. Calcd. for C
3
Acknowledgments.
H N O S: C, 60.29; H, 6.92; N, 7.40; S,
19 26 2 4
We wish to thank Dr. J-H Kim for providing the X-ray crystal-
lography data. This work was supported by the Korea Ministry of
Science and Technology, Kolon Ltd. and KOSEF (R03-2001-
000-00025-0) research projects.
8.47. Found: C, 59.93; H, 6.97; N, 7.34; S, 8.42.
3-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-3a,4,5,6a-tetrahy-
drofuro[3,2-d]isoxazole Tosylate (8b).
This compound was obtained as white powder, yield 33 %, mp
137-138°; ir (potassium bromide): 3460 (SO H), 3040 (CH),
REFERENCES AND NOTES
3
-1
1
1235 cm ; H nmr (CD OD): δ 7.73, 7.28 (ABq, 4H, arom. H),
3
6.24 (d, 1H, C6a-H), 6.23 (m, 1H, C3'-H), 4.10 (m, 3H, C3a-H,
C2'-H), 3.88, 3.66 (m, 2H, C5-H), 3.47, 3.28 (m, 2H, C6'-H),
[1] L. Jeppesen, P. H. Olesen, L. Hansen, M. J. Sheardown, C.
Thomsen, T. Rasmussen, A. F. Jensen, M. S. Christensen, K. Rimvall, J. S.
Ward, C. Whitesitt, D. O. Calligaro, F. P. Bymaster, N. W. Delapp, C. C.
Felder, H. E. Shannon, and P. Sauerberg, J. Med. Chem., 42, 1999 (1999).
[2a] D. W. Gil and B. B. Wolfe, J. Pharmacol. Exo. Ther., 232, 608
(1985); [b] S. K. Fisher, and B. W. Agranoff, J. Neurochem., 48, 999
(1987).
3.02 (s, 3H, NCH ), 2.79 (m, 2H, C5'-H), 2.41 (s, 3H, CH ), 2.15
3
3
13
(m, 2H, C4-H); C nmr (CD OD): δ 159.4 (C-3), 143.7, 142.2,
3
130.2, 127.2 (arom. C), 128.4 (C-4'), 125.3 (C-3'), 111.6 (C-6a),
[3] R. M. Moltzen, R. E. Pederson, K. P. Bogeso, E. Meier,
K. Frederiksen, C. Sanchez and H. L. Lembol, J. Med. Chem., 37, 4085
(1994).
Table
Crystal Data and Structure Refinement for 3b
[4] E. Toja, C. Bonetti and A. Butti, Eur. J. Med. Chem., 27, 519
(1992).
[5a] J. E. Christie, A. Shering, J. Ferguson and A. I. Glen, Br.
J. Psychiatry, 138, 46 (1981); [b] J. M. Palacios and R. Spiegel, Prog.
Brain Res., 70, 485 (1986).
Empirical formula
Formula weight
Temperature
C
H
N O
10 10 2 2
190.20
297(2) K
0.71073 Å
Wavelength
Crystal system, space group
Unit cell dimensions
Monoclinic, P2 /c
a = 9.635(2) Å α = 90°
[6a] M. H. Jung, J.-G. Park, B.-S. Ryu and K.-W. Cho,
J. Heterocyclic Chem., 36, 429 (1999); [b] M. H. Jung, J.-G. Park, K.-W.
Cho and H.-G. Cheon, Korean J. Med. Chem., 9, 8 (1999).
[7] M. H. Jung, S.-W. Choi and K.-W. Cho, J. Heterocyclic
Chem., 37, 969 (2000).
[8] T. Tatee, S. Kurashige, A. Shiozawa, K. Narita, M. Takei,
S. Ito, H. Miyazaki, H. Yamanaka, M. Mizugaki, T. Sakamodo and
H. Fukada, Chem. Pharm. Bull., 34, 1634 (1986).
1
b = 11.799(2) Å β = 117.354(15)°
c = 9.0545(13) Å γ = 90°
3
Volume, Z
914.3(3) Å , 4
3
Calculated density
Absorption coefficient
F(000)
1.382 Mg/m
0.099 mm
-1
400
Crystal size
θ range for data collection
Limiting indices
Reflections collected
Independent reflections
Refinement method
Data/restraints/parameters
Goodness-of-fit on F
Final R indices [I>2σ(I)]
R indices (all data)
Extinction coefficient
Largest diff. peak and hole
0.40 x 0.26 x 0.21 mm
2.38 to 26.50°
-12 ≤ h ≤ 11, -1 ≤ k ≤ 14, -1 ≤ l ≤ 11
2423
[9] G. D. Diana, P. Rudewicz, D. C. Pevear, T. J. Nitz,
S. C. Aldous, D. J. Aldous, D. T. Robinson, T. Draper, F. J. Dutko,
C. Aldi, G. Gendron, R. C. Oglesby, D. L. Volkots, M. Reuman,
T. R. Bailey, R. Czerniak, T. Block, R. Roland and J. Oppermann, J. Med.
Chem., 38, 1355 (1995).
1868 [R = 0.0725]
int
2
Full-matrix least-squares on F
1868 / 0 / 128
1.094
[10] I. Yamawaki, and K. Ogawa, Chem. Pharm. Bull., 36, 3142
(1988).
2
[11a] U. Chiacchio, A. Corsaro, V. Librando, A. Rescifina, R.
Romeo and G. Romeo, Tetrahedron, 52, 14323 (1996); [b] M. L. Quan,
C. D. Ellis, A. Y. Liauw, R. S. Alexander, R. M. Knabb, G. Lam, M. R.
Wright, P. C. Wong and R. R. Wexler, J. Med. Chem., 42, 2760 (1999); [c]
J. T. Pulkkinen and J. Vepaelaeinen, J. Org. Chem., 61, 8604 (1996).
R1 = 0.0855, wR2 = 0.2479
R1 = 0.1256, wR2 = 0.2988
0.015(10)
-3
0.283 and -0.453 e.A

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1,2,5,6-/1,2,3,6-Tetrahydropyridinyl-tetrahydrocyclopentaisoxazole Derivatives
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[12] M. H. Jung, J.-G. Park, J.-S Oh and H.-G. Cheon, Korean J.
Med. Chem., 8, 38 (1998).
[13] T. Aftab, R. Grigg, M. Landlow, V. Sridharan and M.
Thornton-Pett, Chem. Commun., 1754 (2002).