Synthesis of 3-[4-acyl-2-(1-methoxy-1-methylethyl)morpholin-3-yl]- benzonitriles as novel potassium channel openers

Article abstract of DOI:10.1002/jccs.200400024

Potassium channel openers (KCO's) have been demonstrated to possess potent relaxant-activity on smooth muscle. Tissue-selective KCO's may find use in the treatment of a variety of diseases, such as hypertension, asthma, and urinary incontinence. We have p

Full text of DOI:10.1002/jccs.200400024

Journal of the Chinese Chemical Society, 2004, 51, 157-165
157
Synthesis of 3-[4-Acyl-2-(1-methoxy-1-methylethyl)morpholin-3-yl]-
benzonitriles as Novel Potassium Channel Openers
Mei-Shan Lina,b
(
), Ling-Wei Hsina* (
) and Chen-Yu Chenga§
(
)
aSchool of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan, R.O.C.
bDepartment of Biochemistry, College of Medicine, Taipei Medical University, Taipei, Taiwan, R.O.C.
Potassium channel openers (KCO’s) have been demonstrated to possess potent relaxant-activity on
smooth muscle. Tissue-selective KCO’s may find use in the treatment of a variety of diseases, such as hyper-
tension, asthma, and urinary incontinence. We have previously reported a series of 1,9-dioxa-4-aza-phen-
anthrene-6-carbonitriles, including compounds 2 & 3, as bladder-selective KCO’s. As a continuation of our
efforts, we have designed 3-[4-acyl-2-(1-methoxy-1-methylethyl)morpholin-3-yl]-benzonitriles as ring-
opened analogs of compounds 2 & 3. In this report, we describe the efficient construction of the novel
2,3-disubstituted morpholine structure, as represented by the synthesis of compounds 4-7. Compounds 4-7
showed potent and selective relaxant-activity on rat bladder detrusor strip preparation. In this series, the most
potent derivatives are Boc-substituted analogs 4 & 6 (IC50 = 3.9 and 2.9 mM, respectively).
Keywords: Potassium channel opener; Cromakalim; Synthesis; Morpholine; DAST.
INTRODUCTION
Chart 1
The potassium channel openers (KCO’s) are chemi-
cally heterogeneous agents which relax smooth muscle by
opening potassium channels in the cell membrane.1-4 KCO’s
hold therapeutic promise as antianginals, cardioprotectives,
bronchodilators, and agents against urinary incontinence.5-12
Some KCO’s have been introduced in the clinic as antihy-
pertensive agents. Cromakalim ((±)-1) is a prototype KCO,2
which lacks tissue selectivity, therefore, limiting its clinical
potential.13 Tissue-selective KCO’s that selectively activate
potassium channels in the bladder may be potential therapeu-
tics for the treatment of urge urinary incontience.14-18 In our
previous study, we synthesized a series of 1,9-dioxa-4-aza-
phenanthrene-6-carbonitriles,19,20 as represented by com-
pounds 2 & 3 (Chart 1). These compounds were designed on
the basis of rigidization of the amide function and the 3-hy-
droxy group in 1. Compound 2, the N-benzoyl derivative, has
been identified as a bladder-selective KCO, while its cis iso-
mer 3 was found to be more potent than 2 (IC50, bladder = 8.2
mM, IC50, portal vein = 35 mM). In an effort to further study the
structure activity relationship of 3 and related compounds,
we synthesized compounds 4-7, which can be viewed as
ring-opened analogs of 2 & 3. The KCO activities and selec-
O
N
O
N
O
O
N
O
NC
OH
NC
O
NC
O
O
(+)-1: Cromakalim
(-)-1: Levcromakalim
(+)-2
(-)-3
R
R
O
N
3
O
N
3
NC
O
NC
O
2
2
MeO
MeO
4: R = OC(CH3)3
5: R = C6H5
6: R = OC(CH3)3
7: R = C6H5
tivity of target compounds 4-7 were determined by in vitro
tissue assays, spontaneously contracting rat portal vein and
KCl-stimulated rat detrusor strip preparations.
RESULTS AND DISCUSSION
The synthetic strategy for target compounds 4-7 was
§ Current address: Formosa Laboratories, Inc., No. 36-1, Hoping Street, Louchu Country, Taoyuan, Taiwan 338, R.O.C.
* Corresponding author. Tel: +886-2-2395-2310; fax: +886-2-2351-2086; e-mail: lwh@ha.mc.ntu.edu.tw

158 J. Chin. Chem. Soc., Vol. 51, No. 1, 2004
Lin et al.
modeled after the synthesis of 2 & 3 as shown in Scheme I. In
our previous study, we found that compound 2 can be con-
verted smoothly to its cis isomer 3 upon treatment with
base.19,20 Therefore, we expected to obtain the desired cis
compounds 6 & 7 from their trans isomers 4 & 5 via base-
catalyzed epimerization. The key intermediate morpholine 8
could be derived from cis-olefin 11 via epoxidation, nucleo-
philic ring opening, followed by cyclization. Compound 11
could be obtained from alkyne 12 via partial hydrogenation,
which leads to 3-bromobenzonitrile (13) and 2-methyl-3-
butyn-2-ol (14) as starting materials. Therefore, compound
13 was coupled with 14 under Heck condition21 to give acety-
lene 12 in 90% yield (Scheme II). Partial hydrogenation of
alkyne 12 with the Lindlar catalyst then provided cis alkene
15, which was methylated with CH3I/NaH to give methyl
ether 11 in good yield. Epoxidation of olefin 11 with m-
CPBA yielded epoxide 10 in 76% yield.
pound 4 with stannic chloride23 gave the corresponding
morpholine 8, which was acylated with benzoyl chloride/
Et3N to provide target compound 5 in satisfactory yield. The
trans configuration of 4 & 5 was confirmed by their 1H-NMR
spectra, which showed a coupling constant of 9 Hz between
the protons at C-2 and C-3.
However, unlike what was observed with compounds 2
& 3, we failed to convert compounds 4 & 5 to the correspond-
ing cis isomers 6 & 7 under various basic conditions. There-
fore, the alternative approach as shown in Scheme III, with
(diethylamino)sulfur trifluoride (DAST)-effected hydroxyl
inversion24 as the key step, was followed. Thus, compound 16
was treated with acetic anhydride in pyridine to afford
acetamide 21 in 56% yield. Treatment of 21 with DAST, fol-
lowed by hydrolysis of the intermediate acetate, then gave
aminoalcohol 20 in 31% yield. cis-Aminoalcohol 20 was then
subjected to the same reaction sequence as described for the
synthesis of 5 from 16, with the successful generation of tar-
get compounds 6 & 7 (Scheme IV). The cis configuration of 6
& 7 was confirmed by 1H-NMR of 19, which showed a cou-
pling constant of 3 Hz between the protons at C-2 and C-3.
The KCO activities and selectivity of compounds 4-7
were evaluated in vitro with preparations of spontaneously
contracting rat portal vein and KCl-stimulated rat detrusor
strip by the literature procedures.16 All new compounds dem-
onstrated potent and selective relaxant-activity on bladder
detrusor (Table 1). Unlike the structure-activity relationship
(SAR) in the series of compounds (+)-2 and (-)-3, the trans
isomers 4 & 5 showed quite similar KCO activities and selec-
Initially, epoxide 10 was treated with 2-aminoethanol
to construct the desired morpholine ring and provided the
diol intermediate 9 in low yield (20%). Furthermore, when
compound 9 was subjected to Mitsunobu reaction condition
(Et3P/DEAD),22 only a trace amount of morpholine 8 was ob-
tained. Thus, an alternative approach using an allyl group as a
masked hydroxyethyl moiety was adopted. Epoxide 10 was
reacted with allylamine in DMSO to give aminoalcohol 16 in
52% yield. Compound 16 was converted to diol 18 via treat-
ment with (Boc)2, ozonolysis, and NaBH4 reduction. Treat-
ment of the N-protected 18 with Et3P/DEAD then provided
the desired morpholine 4 in 90% yield. Deprotection of com-
Scheme I
OH
HN
HN
NC
N
O
N
O
NC
OH
O
NC
O
NC
O
MeO
MeO
MeO
MeO
8
9
7
5
NC
Br
O
NC
OH
NC
NC
13
MeO
MeO
+
11
12
10
H
OH
14

Potassium Channel Openers
J. Chin. Chem. Soc., Vol. 51, No. 1, 2004 159
Scheme II
OH
NC
c
NC
NC
NC
Br
a
b
MeO
HO
12
13
11
15
O
N
O
HN
f
NC
O
g
e
NC
OH
d
NC
OH
MeO
MeO
MeO
16
10
17
O
OH
O
HN
N
h
O
NC
O
j
N
i
O
O
N
NC
OH
NC
O
NC
O
MeO
MeO
MeO
MeO
18
8
4
5
base
base
6
7
Reagents and Conditions: (a) 14, Pd(PPh3)2Cl2, CuI, Et3N, 110 oC, 90%; (b) Pd/CaCO3/Pb, H2, MeOH, 90%;
(c) NaH, CH3I, THF, 0 oC, 95%; (d) m-CPBA, CH2Cl2, rt, 76%; (e) allylamine, DMSO, 150 oC, 52%; (f) (Boc)2O,
K2CO3, THF, 60 oC, 60%; (g) O3, CH2Cl2, -78 oC; then NaBH4, CH3OH, rt; 70%; (h) Et3P, DEAD, THF, rt, 90%;
(i) SnCl4, CH2Cl2, rt, 87%; (j) benzoyl chloride, Et3N, THF, 0 oC, 52%.
tivity as the cis isomers 6 & 7 in this novel series of ring-
opened analogs. Replacing the phenyl substituent on com-
pounds 5 & 7 with Boc group significantly increased the re-
laxant-activity on bladder detrusor and produced the most po-
tent derivatives 4 & 6 in this series of compounds (IC50 = 3.9
and 2.9 mM, respectively).
vices. NMR spectra were recorded on Bruker AMX-200,
AMX-400, and DMX-500 FT-NMR spectrometers; chemical
shifts were recorded in parts per million downfield from
Me4Si. IR spectra were determined with a Perkin-Elmer
1760-X FT-IR spectrometer. Mass spectra were recorded on
Jeol JMS-D300 and FINNIGAN TSQ-46C mass spectrome-
ters; HRMS was obtained with a Jeol JMS-HX110 spectrom-
eter. TLC was performed on Merck (Art. 5715) silica gel
plates and visualized under UV light (254 nm), upon treat-
ment with iodine vapor, or upon heating after treatment with
5% phosphomolybdic acid in ethanol. Flash column chroma-
tography was performed with Merck (Art. 9385) 40-63 mm
silica gel 60. Elemental analyses were carried out on a
Perkin-Elmer 240 elemental analyzer and the results were
Further pharmacological evaluation and SAR studies
are in progress and will be reported in due course.
EXPERIMENTAL SECTION
Melting points were taken in a capillary tube by using a
MEL-TEMP II melting point apparatus by Laboratory De-

160 J. Chin. Chem. Soc., Vol. 51, No. 1, 2004
Lin et al.
Scheme III
HN
N
O
HN
NC
O
NC
O
NC
OH
MeO
MeO
MeO
19
7
20
O
N
HN
NC
OH
NC
OH
MeO
MeO
21
16
Scheme IV
O
HN
N
HN
b
d
a
NC
OH
NC
NC
OR
OH
MeO
MeO
MeO
16
22: R = Ac
20: R = H
21
c
O
O
O
N
OH
g
N
O
N
e
O
O
f
NC
O
NC
NC
OH
OH
MeO
MeO
MeO
24
6
23
HN
NC
O
h
O
N
NC
O
MeO
MeO
19
7
Reagents and Conditions: (a) Ac2O, pyridine, rt, 56%; (b) DAST, CH2Cl2, 0 oC, 49%; (c) NaOH,
CH3OH, rt, 30 min, 31% (two steps); (d) (Boc)2O, K2CO3, THF, 60 oC, 47%; (e) O3, CH2Cl2, -78
oC; then NaBH4, CH3OH, rt; 72%; (f) Et3P, DEAD, THF, rt, 40%; (g) SnCl4, CH2Cl2, rt, 87%; (h)
benzoyl chloride, Et3N, THF, 0 oC, 80%.

Potassium Channel Openers
J. Chin. Chem. Soc., Vol. 51, No. 1, 2004 161
3200~3600, 2250 cm-1; 1H NMR (200 MHz, CDCl3) d 1.31 (s,
6H), 1.73 (s, 1H), 5.77 (d, J = 12.7 Hz, 1H), 6.30 (d, J = 12.8
Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.59
(d, J = 7.8 Hz, 1H), 7.64 (s, 1H); 13C NMR (50 MHz, CDCl3)
d 31.5, 72.5, 112.2, 119.4, 126.3, 128.9, 130.7, 133.3, 134.3,
139.2, 141.4; MS (EI, 70 eV) m/z 187 (M+), 154 (base);
HRMS (EI) Calcd. for C12H13NO+: 187.1002, found 187.1000.
Table 1. Mechanoinhibitory Activities of Compounds 4-7 (IC50
SD, mM)a
±
Compound
Portal veinb
Detrusorc
IC50 ratiod
e
(+)-2
(-)-3
4
5
6
7
+
66 ± 20
8.2 ± 2
3.9 ± 0.8
18 ± 5
2.9 ± 2
23 ± 0.1
0.29 ± 0.01
NDf
4.2
35 ± 0.7
e
+
+
+
+
NDf
NDf
NDf
NDf
0.31
e
e
e
cis-3-(3-Methoxy-3-methyl-1-butenyl)benzonitrile (11)
To a solution of 15 (1.90 g, 10.2 mmol) in THF (20 mL),
NaH (0.81 g, 20.3 mmol) and CH3I (1.26 mL, 20.3 mmol)
were added and stirred at 0 °C for 6 h. The mixture was
quenched with H2O and extracted with CH2Cl2. The com-
bined extract was washed with aqueous 1N NaOH, H2O, and
brine, dried (MgSO4) and evaporated to afford 11 (2.00 g,
98%). Rf 0.70 (EtOAc/n-hexane = 1/3); IR (neat) 2250 cm-1;
1H NMR (200 MHz, CDCl3) d 1.27 (s, 6H), 2.96 (s, 3H), 5.59
(d, J = 13.0 Hz, 1H), 6.37 (d, J = 13.0 Hz, 1H), 7.31~7.48 (m,
2H), 7.65-7.71 (m, 2H); 13C NMR (50 MHz, CDCl3) d 27.7,
50.5, 76.0, 112.2, 119.3, 128.4, 128.9, 130.7, 133.4, 134.4,
138.8, 138.9; MS (EI, 70 eV) m/z 201 (M+, base); HRMS (EI)
Calcd. for C13H15NO+: 201.1154, found 201.1154.
levcromakalim
0.09 ± 0.01
a Data represents the mean of three experiments each performed
in duplicate. b Spontaneously contracting rat portal vein. c Isolated
rat detrusor strips exposed to extracellular KCl (20 mM). d IC50,
portal vein/IC50, bladder. e The “+” sign indicates no inhibition was
observed at the concentration range tested (0.01-100 mM), but an
increase in the frequency of the spontaneous contraction was
observed at high concentrations (³ 30 mM). f Not determined.
within ± 0.4% of theoretical values. Anhydrous tetrahydro-
furan was distilled from sodium-benzophenone prior to use.
3-(3-Hydroxy-3-methyl-1-butynyl)benzonitrile (12)
A mixture of 3-bromobenzonitrile (13, 6.00 g, 32.9
mmol), 2-methyl-3-butyn-2-ol (14, 4.0 mL, 41.1 mmol),
dichlorobis(triphenylphosphine)palladium (1.12 g, 5 mol%),
and CuI (0.61 g, 10 mol%) in Et3N (200 mL) was degassed
and then heated to 110 °C in a sealed flask for 3 h. After it
cooled, the solution was filtered and evaporated. The residue
was dissolved in CH2Cl2 (400 mL) and treated with activated
charcoal. The mixture was filtered, evaporated, and chroma-
tographed on silica gel (CH2Cl2) to afford 12 (5.47 g, 90%) as
a colorless oil. Rf 0.18 (CH2Cl2); IR (neat) 3200~3600, 2250
cm-1; 1H NMR (400 MHz, CDCl3) d 1.59 (s, 6H), 2.15 (s, 1H),
7.39 (d, J = 6.3 Hz, 1H), 7.56 (d, J = 6.3 Hz, 1H), 7.60 (d, J =
6.3 Hz, 1H), 7.66 (s, 1H); 13C NMR (100 MHz, CDCl3) d
31.3, 65.5, 79.8, 96.3, 112.8, 118.0, 124.4, 129.2, 131.4, 134.9,
135.7; MS (EI, 70 eV) m/z 185 (M+), 170 (base peak); HRMS
(EI) Calcd. for C12H11NO+: 185.0815, found 185.0828.
3-[3-(1-Methoxy-1-methyl-ethyl)-oxiranyl]benzonitrile
(10)
To a stirred solution of 11 (2.14 g, 11.4 mmol) in
CH2Cl2 (50 mL) was added m-chloroperbenzoic acid (4.23 g,
70% in water) and the mixture was stirred at ambient temper-
ature for 24 h. The precipitate was filtered off and the filtrate
was washed with aqueous Na2SO3 followed by aqueous
NaHCO3. The dried (MgSO4) organic phase was evaporated
and chromatographed on silica gel (EtOAc/n-hexane = 1/3)
to afford 10 (1.72 g, 75%) as an oil. Rf 0.43 (EtOAc/n-hexane
1
= 1/3); IR (neat) 2250 cm-1; H NMR (200 MHz, CDCl3) d
0.71 (s, 3H), 1.02 (s, 3H), 3.19 (s, 3H), 3.22 (d, J = 4.5 Hz,
1H), 3.99 (d, J = 4.5 Hz, 1H), 7.37~7.62 (m, 4H); 13C NMR
(50 MHz, CDCl3) d 22.0, 24.4, 51.0, 55.2, 65.4, 74.5, 112.6,
118.9, 129.2, 130.6, 131.4, 131.5, 137.5; MS (EI, 70 eV) m/z
217 (M+), 186 (base); HRMS (EI) Calcd. for C13H15NO2 :
+
cis-3-(3-Hydroxy-3-methyl-1-butenyl)benzonitrile (15)
A solution of 12 (0.68 g, 3.68 mmol) and quinoline (1
mL) in anhydrous CH3OH (30 mL) was hydrogenated at at-
mospheric pressure over 5% Pd/CaCO3/Pb (0.3 g) until 1
equiv of H2 was absorbed. The mixture was filtered, diluted
with CH2Cl2 (30 mL), and washed with 2M HCl. The CH2Cl2
layer was dried (MgSO4), evaporated, and chromatographed
on silica gel (EtOAc/n-hexane = 1/10) to afford 15 (0.62 g,
90%) as an oil. Rf 0.68 (EtOAc/n-hexane = 1/3); IR (neat)
217.1103, found 217.1103.
3-[2-Hydroxy-1-(2-hydroxy-ethylamino)-3-methoxy-3-
methylbutyl]benzonitrile (9)
A solution of epoxide 10 (0.60 g, 2.76 mmol) and
ethanolamine (1.35 mL, 22.1 mmol) in THF (10 mL) was
refluxed under N2 overnight. The reaction mixture was evap-
orated and chromatographed on silica gel (CH2Cl2/CH3OH/

162 J. Chin. Chem. Soc., Vol. 51, No. 1, 2004
Lin et al.
NH4OH = 100/10/1) to afford 9 (0.15 g, 20%) as an oil. Rf
0.30 (CH2Cl2/CH3OH/NH4OH = 100/10/1); IR (neat) 3315,
2228 cm-1; 1H NMR (200 MHz, CDCl3) d 1.08 (s, 3H), 1.15
(s, 3H), 2.19 (s, 3H), 2.40~2.54 (m, 2H), 3.11 (s, 3H), 3.32 (d,
J = 3.7 Hz, 1H), 3.55 (m, 2H), 3.86 (d, J = 3.7 Hz, 1H),
7.36~7.75 (m, 4H); 13C NMR (50 MHz, CDCl3) d 21.4, 21.8,
48.7, 49.2, 61.2, 62.4, 77.8, 79.7, 112.2, 118.8, 129.1, 130.8,
131.6, 132.4, 144.2; MS (FAB) m/z 279 (MH+, base); FAB-
[1-(3-Cyanophenyl)-2-hydroxy-3-methoxy-3-methylbutyl]-
(2-hydroxyethyl)carbamic acid tert-butyl ester (18)
A solution of 17 (2.7 g, 7.5 mmol) in CH2Cl2 (40 mL)
was treated with O3 for 5 min at -78 °C, and then evaporated
under reduced pressure. The residue was dissolved in CH3OH
(40 mL), and then NaBH4 (0.34 g, 9.0 mmol) was added to
this solution. The mixture was evaporated, treated with H2O,
and extracted with CH2Cl2. The extract was washed with H2O
and brine, dried (MgSO4), evaporated, and chromatographed
on silica gel (EtOAc/n-hexane = 1/4) to afford 18 (2.00 g,
70%) as a pale-yellow oil. Rf 0.31 (EtOAc/n-hexane = 1/3);
IR (neat) 3600~3200, 2230, 1691 cm-1; 1H NMR (500 MHz,
CDCl3) d 1.09 (s, 3H), 1.21 (s, 3H), 1.45 (s, 9H), 3.01 (d, J =
13 Hz, 2H), 3.18 (s, 3H), 3.55 (s, broad, 1H), 3.60 (s, broad,
1H), 3.91 (s, broad, 2H), 7.40 (t, J = 8.0 Hz, 1H), 7.52 (d, J =
8.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H); 13C NMR
(125 MHz, CDCl3) d 21.8, 29.0, 49.7, 49.9, 62.1, 77.2, 77.8,
79.6, 81.5, 113.1, 119.3, 129.8, 131.6, 132.7, 133.6, 142.5,
157.5; MS (FAB) m/z 379 (MH+); FAB-HRMS Calcd. for
+
HRMS Calcd. for C15H23N2O3 : 279.1708, found 279.1709.
3-(1-Allylamino-2-hydroxy-3-methoxy-3-methylbutyl)-
benzonitrile (16)
A mixture of epoxide 10 (1.00 g, 4.61 mmol), dimeth-
ylsulfoxide (DMSO, 5.00 mL) and allylamine (3.50 mL, 46.1
mmol) in a sealed flask was heated to 150 °C under N2 for 48
h. After it cooled, DMSO was removed by Kugelrohr distilla-
tion, and then the residue was treated with H2O and extracted
with CH2Cl2. The extract was washed with H2O, and brine,
dried (MgSO4), evaporated and chromatographed on silica
gel (EtOAc) to afford 16 (0.79 g, 65%) as an oil. Rf 0.66
+
C20H31N2O5 : 379.2223, found 379.2229.
1
(EtOAc); IR (neat) 3315, 2228 cm-1; H NMR (200 MHz,
CDCl3) d 1.12 (s, 3H), 1.18 (s, 3H), 2.81~3.02 (m, 4H), 3.15
(s, 3H), 3.28 (d, J = 3.0 Hz, 1H), 3.92 (d, J = 3.0 Hz, 1H), 5.01
(s, 1H), 5.07 (s, 1H), 5.76 (m, 1H), 7.35~7.63 (m, 4H); 13C
NMR (50 MHz, CDCl3) d 22.4, 22.6, 49.8, 53.2, 69.1, 70.0,
78.3, 112.6, 116.9, 119.5, 129.3, 129.6, 130.4, 130.7, 136.3,
147.9; MS (FAB) m/z 275 (MH+, base); FAB-HRMS Calcd.
trans-3-(3-Cyanophenyl)-2-(1-methoxy-1-methylethyl)-
morpholine-4-carboxylic acid tert-butyl ester (4)
To a stirred solution of 18 (175 mg, 0.46 mmol) and
triethylphosphine (0.93 mL, 1 M in THF) in THF (5 mL) was
added dropwise diethyl azodicarboxylate (0.41 mL, 40% in
toluene) at room temperature under N2. The resulting mixture
was stirred at room temperature for 30 min. The mixture was
evaporated and chromatographed on silica gel (EtOAc/n-
hexane = 1/3) to afford 4 (133 mg, 80%) as an oil. mp: 76-77
°C (n-hexane); Rf 0.78 (EtOAc/n-hexane = 1/3); IR (neat)
2229, 1696 cm-1; 1H NMR (200 MHz, CDCl3) d 1.17 (s, 6H),
1.39 (s, 9H), 3.17 (s, 3H), 3.23 (t, J = 5.0 Hz, 1H), 3.38~3.43
(m, 1H), 3.69 (d, J = 2.0 Hz, 1H), 3.72~3.94 (m, 2H), 5.42 (d,
J = 2.0 Hz, 1H), 7.33~7.50 (m, 3H), 7.56 (s, 1H); 13C NMR
(50 MHz, CDCl3) d 19.3, 22.6; 28.8, 41.1, 49.5, 51.2, 61.5,
77.6, 80.8, 84.3, 112.8, 119.4, 129.7, 130.6, 130.8, 131.6,
145.7, 155.5; MS (FAB) m/z 361 (MH+); FAB-HRMS Calcd.
+
for C16H23N2O2 : 275.1761, found 275.1754.
Allyl-[1-(3-cyanophenyl)-2-hydroxy-3-methoxy-3-methyl-
butyl]carbamic acid tert-butyl ester (17)
To a solution of 16 (2.56 g, 9.34 mmol) in THF (20 mL),
K2CO3 (1.94 g, 14.0 mmol) and (Boc)2O (4.20 g, 18.7 mmol)
were added and stirred at 50 °C for 24 h. The mixture was
evaporated, treated with H2O, and extracted with CH2Cl2.
The extract was washed with H2O and brine, dried (MgSO4),
evaporated and chromatographed on silica gel (EtOAc/n-
hexane = 1/3) to afford 17 (1.70 g, 50%) as an oil. Rf 0.74
(EtOAc/n-hexane = 1/3); IR (neat) 3500~3000, 2230, 1681
cm-1; 1H NMR (200 MHz, CDCl3) d 1.76 (s, 6H), 1.42 (s, 9H),
3.17 (s, 3H), 3.63~3.82 (m, 2H), 3.98 (s, 1H), 4.87 (s, 1H),
4.94 (s, 1H), 5.13 (s, 1H), 5.59 (m, 1H), 7.33 (t, J = 8.0 Hz,
1H), 7.37 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.78 (s,
1H); 13C NMR (50 MHz, CDCl3) d 20.0, 22.2, 28.7, 49.4,
50.1, 60.2, 72.3, 78.2, 81.3, 112.7, 117.2, 119.3, 129.4, 131.1,
132.5, 133.5, 135.1, 142.7, 157.6; MS (FAB) m/z 375 (MH+,
+
for C20H29N2O4 : 361.2127, found 361.2122. Anal. Calcd for
C20H28N2O4: C, 66.64; H, 7.83; N, 7.77. Found: C, 66.30; H,
7.64; N, 7.83.
trans-3-[2-(1-Methoxy-1-methylethyl)morpholin-3-yl]-
benzonitrile (8)
To a stirred solution of 4 (0.50 g, 1.4 mmol) in CH2Cl2
was added stannic chloride (1.45 g, 5.6 mmol) at room tem-
perature and stirred for 30 min. The solvent and the excess
SnCl4 were evaporated. The residue was dissolved in
+
base); FAB-HRMS Calcd. for C21H31N2O4 : 375.2283, found
375.2281.

Potassium Channel Openers
J. Chin. Chem. Soc., Vol. 51, No. 1, 2004 163
CH3OH, and then ether was added to afford the HCl salt of
8 as a white precipitate (0.36 g, 87%). Rf 0.32 (CH2Cl2/
CH3OH/NH4OH = 100/10/1); IR (neat) 2233 cm-1; 1H NMR
(200 MHz, CDCl3) d 0.88 (s, 3H), 1.08 (s, 3H), 1.71 (s, 1H),
2.79 (s, 3H), 2.85 (dd, J = 11, 2.0 Hz, 1H), 2.98 (dt, J = 11, 3.0
Hz, 1H), 3.40 (d, J = 9.0 Hz, 1H), 3.70 (dt, J = 11, 3.0 Hz, 1H),
3.82 (d, J = 9.0 Hz, 1H), 3.94 (dd, J = 11, 2.0 Hz, 1H), 7.36 (t,
J = 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz,
1H), 7.69 (s, 1H); 13C NMR (50 MHz, CDCl3) d 22.2, 24.0,
46.7, 49.2, 62.0, 68.4, 77.0, 85.5, 112.3, 119.4, 129.1, 131.3,
132.5, 133.6, 144.6; MS (FAB) m/z 261 (MH+, base); FAB-
1H), 7.87 (s, 1H); 13C NMR (125 MHz, CDCl3) d 19.8, 20.9,
22.0, 22.6, 22.9, 48.9, 49.1, 60.2, 76.5, 77.3, 112.2, 117.4,
118.7 129.0, 130.9, 131.2, 132.2, 133.0, 133.2, 133.6, 141.7,
173.1; MS (FAB) m/z 317 (MH+); FAB-HRMS Calcd. for
+
C18H25N2O3 : 317.1865, found 317.1876.
3-(1-Allylamino-2-hydroxy-3-methoxy-3-methylbutyl)-
benzonitrile (20)
A solution of 21 (2.9 g, 9.2 mmol), diethylaminosulfur
trifluoride (DAST, 1.45 mL, 11.02 mmol) and CH2Cl2 (220
mL) was stirred at room temperature under N2 for 30 min.
The mixture was evaporated, dissolved in 2M NaOH in
CH3OH (20 mL), stirred at room temperature for 10 min, and
then evaporated. The residue was dissolved in CH2Cl2, and
the resultant mixture was washed with H2O and brine, dried
(MgSO4), evaporated, and chromatographed on silica gel
(EtOAc/n-hexane = 2/3) to afford 20 (778 mg, 31%) as an oil.
Rf 0.34 (EtOAc/n-Hexane = 2/3); IR (neat) 3315, 2228 cm-1;
1H NMR (500 MHz, CDCl3) d 1.00 (s, 3H), 1.05 (s, 3H), 2.81
(dd, J = 14.2, 6.6 Hz, 2H), 2.92 (ddd, J = 14.0, 4.0, 1.3 Hz,
1H), 3.09 (s, 3H), 3.60 (d, J = 6.0 Hz, 1H), 3.74 (d, J = 6.0 Hz,
1H), 4.97 (d, J = 1.0 Hz, 1H), 4.99 (m, 1H), 5.72 (m, 1H), 7.33
(t, J = 8.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0
Hz, 1H), 7.63 (s, 1H); 13C NMR (125 MHz, CDCl3) d 20.1,
21.9, 48.7, 49.3, 63.0, 77.8, 111.7, 115.9, 118.8, 128.5, 130.6,
132.5, 133.5, 136.2, 143.3; MS (FAB) m/z 275 (MH+, base);
+
HRMS Calcd. for C15H21N2O2 : 261.1603, found 261.1601.
trans-3-[4-Benzoyl-2-(1-methoxy-1-methylethyl)morpholin-
3-yl]benzonitrile (5)
Compound 8 (100 mg, 0.34 mmol) in THF (6 mL) was
reacted with triethylamine (80 mL, 0.58 mmol) and benzoyl
chloride (54 mL, 0.46 mmol) at 0 °C under N2 for 0.5 h and
evaporated under reduced pressure. The residue was dis-
solved in CH2Cl2, washed with 10% NaHCO3, 10% HCl,
H2O, and brine, dried (MgSO4), evaporated, and chromato-
graphed on silica gel (EtOAc/n-hexane = 1/3) to afford 5 (64
mg, 52%) as an oil. Rf 0.19 (EtOAc/n-hexane = 1/3); IR
1
(CH2Cl2) 2229, 1633 cm-1; H NMR (500 MHz, CDCl3) d
1.22 (s, 3H), 1.28 (s, 3H), 1.79 (s, broad, 1H), 3.20 (s, 3H),
3.30 (s, broad, 1H), 3.55 (m, 1H), 3.78 (s, 1H), 4.19 (m, 1H),
5.89 (broad, 1H), 7.35 (m, 5H), 7.46 (t, J = 8.0 Hz, 1H), 7.56
(d, J = 8.0 Hz, 1H), 7.80 (d, broad, 2H); 13C NMR (125 MHz,
CDCl3) d 22.4, 41.9, 49.2, 61.6, 77.3, 78.3, 112.7, 118.8,
126.5, 128.3, 128.5, 129.4, 129.7, 129.9, 130.9, 132.1, 135.8,
143.3, 171.1; MS (FAB) m/z 365 (MH+); FAB-HRMS Calcd.
+
FAB-HRMS Calcd. for C16H23N2O2 : 275.1761, found
275.1762.
Allyl-[1-(3-cyanophenyl)-2-hydroxy-3-methoxy-3-methyl-
butyl]carbamic acid tert-butyl ester (23)
+
for C22H25N2O3 : 365.1866, found 365.1883. Anal. Calcd for
To a solution of 20 (1.50 g, 5.47 mmol) in THF (60 mL),
K2CO3 (1.13 g, 8.20 mmol) and (Boc)2O (2.46 g, 11.0 mmol)
were added and stirred at 50 °C for 24 h. The mixture was
evaporated, treated with H2O, and extracted with CH2Cl2.
The extract was washed with H2O and brine, dried (MgSO4),
evaporated, and chromatographed on silica gel (EtOAc/n-
hexane = 1/3) to afford 23 (0.94 g, 47%) as an oil. Rf 0.62
(EtOAc/n-hexane = 2/3); IR (neat) 3500~3000, 2229, 1685
cm-1; 1H NMR (200 MHz, CDCl3) d 1.11 (s, 3H), 1.17 (s, 3H),
1.42 (s, 9H), 3.18 (s, 3H), 3.65 (m, 1H), 3.86~3.91(m, 2H),
4.08 (s, 1H), 4.86 (d, J = 6.0 Hz, 1H), 4.92 (s, 1H), 5.10 (s,
1H), 5.40 (m, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.50 (d, J = 7.0 Hz,
1H), 7.70 (d, J = 7.0 Hz, 1H), 7.80 (s, 1H); 13C NMR (50
MHz, CDCl3) d 21.5, 28.8, 49.6, 50.1, 60.4, 77.7, 77.8, 81.3,
112.3, 116.8, 119.5, 129.2, 131.4, 134.1, 134.8 135.1, 141.4,
156.3; MS (FAB) m/z 375 (MH+); FAB-HRMS Calcd. for
C22H24N2O3: C, 72.50; H, 6.64; N, 7.69. Found: C, 72.58; H,
6.74; N, 7.62.
N-Allyl-N-[1-(3-cyanophenyl)-2-hydroxy-3-methoxybutyl]-
acetamide (21)
A solution of compound 16 (5.2 g, 19 mmol) and acetic
anhydride (3.2 mL) in pyridine (20 mL) was stirred at 0 °C for
18 h. The mixture was treated with 10% NaOH and extracted
with CH2Cl2. The organic layer was washed with 2N HCl
(100 mL) and then evaporated. The residue was chromato-
graphed (silica gel, EtOAc/n-hexane = 2/3) to afford 21 (3.35
g, 56%) as a light-brown oil. Rf 0.25 (EtOAc/n-hexane = 2:3);
IR (neat) 3500~3200, 2229, 1624 cm-1; 1H NMR (200 MHz,
CDCl3) d 1.17 (s, 3H), 1.21 (s, 3H), 2.13 (s, 3H), 3.21 (s, 3H),
3.90-4.10 (m, 4H), 4.96-5.06 (m, 2H), 5.57 (m, 1H), 7.42 (t, J
= 7.3 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 7.6 Hz,
+
C21H31N2O4 : 375.2283, found 375.2285.

164 J. Chin. Chem. Soc., Vol. 51, No. 1, 2004
Lin et al.
[1-(3-Cyanophenyl)-2-hydroxy-3-methoxy-3-methylbutyl]-
(2-hydroxyethyl)carbamic acid tert-butyl ester (24)
CH2Cl2 was added stannic chloride (438 mg, 1.68 mmol) at
room temperature and stirred for 30 min. The solvent and the
excess SnCl4 were evaporated. The residue was treated with
1N NaOH and extracted with CH2Cl2. The extract was
washed with H2O, and brine, dried (MgSO4), evaporated, and
chromatographed on silica gel (CH2Cl2/CH3OH/NH4OH =
100/10/1) to afford 19 as an oil (94 mg, 87%). Rf 0.32
(EtOAc/n-hexane = 1/3); IR (neat) 2233 cm-1; 1H NMR (500
MHz, CDCl3) d 0.88 (s, 3H), 0.93 (s, 3H), 2.57 (ddd, J = 13,
3.0, 1.0 Hz, 1H), 3.02 (s, 3H), 3.21 (td, J = 12, 4.0 Hz, 1H),
3.79 (d, J = 3.0 Hz, 1H), 3.80 (dt, J = 12, 3.0 Hz, 1H), 3.92 (d,
J = 3.0 Hz, 1H), 4.15(dd, J = 11, 3.0 Hz, 1H), 7.36 (t, J = 8.0
Hz, 1H), 7.51 (dt, J = 8.0, 1.0 Hz, 1H), 7.77 (dd, J = 7.0, 1.0
Hz, 1H), 7.87 (d, J = 1.0 Hz, 1H); 13C NMR (125 MHz,
CDCl3) d 21.6, 22.7, 39.3, 49.2, 56.4, 69.1, 75.9, 85.5, 111.6,
119.0, 128.4, 130.5, 133.3, 134.4, 142.7; MS (FAB) m/z 261
A solution of 23 (0.94 g, 2.6 mmol) in CH2Cl2 (50 mL)
was treated with O3 for 5 min at -78 °C, and then evaporated
under reduced pressure. The residue was dissolved in
CH3OH (40 mL), and then NaBH4 (0.42 g, 5.2 mmol) was
added to this solution. The mixture was evaporated, treated
with H2O, and extracted with CH2Cl2. The extract was
washed with H2O and brine, dried (MgSO4), evaporated, and
chromatographed on silica gel (EtOAc/n-hexane = 1/4) to af-
ford 24 (0.69 g, 72%) as a pale-yellow oil. Rf 0.26 (EtOAc/n-
1
hexane = 2/3); IR (neat) 2230, 1691 cm-1; H NMR (200
MHz, CDCl3) d 1.13 (s, 6H), 1.46 (s, 9H), 3.20 (s, 3H), 3.48
(s, broad, 3H), 4.10 (s, 1H), 5.17 (s, broad, 1H), 7.39 (t, J =
4.0 Hz, 1H), 7.47 (d, J = 7.0 Hz, 1H), 7.73 (d, J = 7.0 Hz, 1H),
7.86 (s, 1H); 13C NMR (125 MHz, CDCl3) d 20.6, 22.5, 28.9.
49.6, 49.7, 61.2, 62.5, 77.5, 78.5, 81.7, 112.6, 119.3, 129.3,
129.4, 131.6, 134.2, 135.1, 141.1, 156.6; MS (FAB) m/z 379
(MH+); FAB-HRMS Calcd. for C15H21N2O2 : 261.1603,
+
found 261.1607.
(MH+); FAB-HRMS Calcd. for C20H31N2O5 : 379.2223,
+
found 379.2236.
cis-3-[4-Benzoyl-2-(1-methoxy-1-methylethyl)morpholin-3-
yl]benzonitrile (7)
cis-3-(3-Cyanophenyl)-2-(1-methoxy-1-methylethyl)-
Compound 19 (54 mg, 0.21 mmol) in THF (10 mL) was
reacted with triethylamine (45 mL, 0.32 mmol) and benzoyl
chloride (29 mL, 0.25 mmol) at 0 °C under N2 for 0.5 h and
evaporated under reduced pressure. To the residue was added
CH2Cl2, and then the mixture was washed with 10% NaHCO3,
10% HCl, H2O, and brine, dried (MgSO4), evaporated, and
chromatographed on silica gel (EtOAc/n-hexane = 1/3) to af-
ford 7 (60 mg, 80%) as an oil. Rf 0.30 (EtOAc/n-hexane =
morpholine-4-carboxylic acid tert-butyl ester (6)
To a stirred solution of 24 (688 mg, 1.82 mmol) and
triethylphosphine (3.6 mL, 1 M in THF) in THF (20 mL) was
added dropwise diethyl azodicarboxylate (634 µL, 40% in to-
luene) at room temperature under N2. The resulting mixture
was stirred at room temperature for 30 min. The mixture was
evaporated and chromatographed on silica gel (EtOAc/n-
hexane = 1/3) to afford 6 (265 mg, 40%) as a solid. mp:
143-144 °C (n-hexane); Rf 0.73 (EtOAc/n-hexane = 1/3); IR
(neat) 2229, 1696 cm-1; 1H NMR (500 MHz, CDCl3) d
0.72~1.06 (m, 6H), 1.35 and 1.39 (s, 9H), 3.02 and 3.04 (s,
3H), 3.32 (m, 1H), 3.61 and 3.62 (s, 1H), 3.67~3.80 (m, 2H),
4.18~4.26 (m, 1H), 4.93 and 5.14 (d, J = 3.0 Hz, 1H ), 7.36
(m, 1H), 7.52 (m, 1H), 7.79 and 7.84 (d, J = 8.0 Hz, 1H), 7.81
and 7.99 (s, 1H); 13C NMR (125 MHz, CDCl3) d 20.5, 21.3;
22.8, 23.7, 28.3, 28.4, 38.5, 39.4, 49.1, 49.2, 53.6, 55.1, 68.0,
68.2, 75.5, 75.6, 80.4, 80.7, 85.3, 85.9, 111.5, 118.9, 119.1,
128.4, 130.9, 133.9, 134.1, 134.7, 135.3, 139.7, 140.4, 154.2,
154.5; MS (FAB) m/z 361 (MH+); FAB-HRMS Calcd. for
1
2/3); IR (CH2Cl2) 2229, 1633 cm-1; H NMR (500 MHz,
CDCl3) d 0.99 (s, 3H), 1.09 (s, 3H), 2.95 and 3.06 (s, 3H),
3.43 (d, J = 13.6 Hz, 1H), 3.59 and 3.84 (t, J = 12.0 Hz, 1H ),
3.67 and 4.35 (m, 1H), 3.71 (s, 1H), 4.15 (d, J = 8.7 Hz, 1H),
4.90 and 5.85 (s, 1H), 7.21~7.78 (m, 7H), 7.98 (d, J = 7.4 Hz,
1H), 8.14 (s, 1H); 13C NMR (125 MHz, CDCl3) d 21.6, 22.8,
42.9, 49.3, 52.3, 68.3, 75.6, 86.0, 111.8, 118.9, 126.8, 128.5,
128.7, 129.9, 131.3, 124.4, 135.3, 135.6, 139.1, 170.0; MS
(FAB) m/z 365 (MH+); FAB-HRMS Calcd. for C22H25N2O3 :
+
365.1866, found 365.1871.
+
C20H29N2O4 : 361.2127, found 361.2124; Anal. Calcd for
ACKNOWLEDGMENTS
C20H28N2O4: C, 66.64; H, 7.83; N, 7.77. Found: C, 66.69; H,
7.88; N, 7.59.
The research grant from the National Science Council
(NSC 90-2320-B-002-206) is highly appreciated.
cis-3-[2-(1-Methoxy-1-methylethyl)morpholin-3-yl]benzo-
nitrile (19)
To a stirred solution of 6 (150 mg, 0.42 mmol) in
Received May 7, 2003.

Potassium Channel Openers
J. Chin. Chem. Soc., Vol. 51, No. 1, 2004 165
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14. Malmgren, A.; Andersson, K. E.; Sjogren, C.; Andersson, P.
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