Preparation of the I3 imidazoline receptor antagonist KU14R and related 2,3-dihydrobenzo[b]furan derivatives

Article abstract of DOI:10.1055/s-2001-16079

The preparation and characterisation of a series of novel analogues of the imidazoline insulin secretagogue efaroxan, including the I₃-receptor antagonist KU14R, are described. Replacement of the imidazoline ring of efaroxan by selected functional groups leads either to loss of activity or to very weak I₃-agonist activity in insulin secretion studies. The imidazole analogue KU14R was found to be an I₃-antagonist in this assay and useful as a biological tool.

Full text of DOI:10.1055/s-2001-16079

1
546
PAPER
Preparation of the I Imidazoline Receptor Antagonist KU14R and Related
3
2
,3-Dihydrobenzo[b]furan Derivatives
a
b
a
P
J
reparatio
.
nof the
I
Im
C
idazoline
R
ecep
l
tor
A
nt
e
agonist
K
U
w
14R s, Noel G. Morgan, Christopher A. Ramsden*
3
a
School of Chemistry and Physics, Keele University, Keele, Staffordshire ST5 5BG, UK
Fax +44(1782)712378; E-mail: c.a.ramsden@chem.keele.ac.uk
b
School of Life Sciences, Keele University, Keele, Staffordshire ST5 5BG, UK
Received 7 March 2001; revised 17 April 2001
tive of mapping the I receptor pharmacophore and iden-
tifying more potent ligands. As part of this work we
3
Abstract: The preparation and characterisation of a series of novel
analogues of the imidazoline insulin secretagogue efaroxan, includ-
prepared the imidazole derivative 14 (KU14R) and have
ing the I -receptor antagonist KU14R, are described. Replacement
3
6
of the imidazoline ring of efaroxan by selected functional groups shown that in both insulin secretion and electrophysio-
7
leads either to loss of activity or to very weak I -agonist activity in logical studies KU14R behaves as an antagonist [EC 30
3
50
insulin secretion studies. The imidazole analogue KU14R was
M] at the I imidazoline binding site, although it is im-
3
found to be an I -antagonist in this assay and useful as a biological
3
portant to note that KU14R also displays weak channel
tool.
7
blocking activity in the absence of efaroxan (1). KU14R
Key words: imidazoline, efaroxan, I -receptor, imidazole, antago-
3
(14) has proved to be a useful biological tool for the study
of insulin secretion mechanisms and further evaluation is
in hand. In this paper we describe the preparation and
chemical characterisation of KU14R and closely related
nist, tetrazole, insulin
It is well known that some imidazoline-containing ligands compounds relevant to mapping the receptor binding re-
have an affinity for binding sites distinct from
-
quirements.
1
adrenoceptors and two discrete imidazoline receptors
Our initial studies have focused on the preparation of efar-
oxan analogues having the general structure 3 (Figure 1).
The simplest analogues of this type are the amides 8 and
2
(
designated I and I ) are well characterised. Recent work
1 2
3
in our laboratories at Keele has identified a third imida-
zoline binding site (putatively designated I ) in pancreatic
3
9
which were prepared from the known carboxylic acids 4
-cells and this receptor is associated with control of insu-
8
and 5. Using similar procedures the secondary and tertia-
ry amides 6 and 7 were also prepared (Scheme 1). The
lin secretion. An endogenous ligand has not been identi-
fied but the imidazoline derivative efaroxan (1) is a
selective agonist [EC 100 M] at the I receptor (versus
amides 6 and 7 did not show I -agonist activity in insulin
3
5
0
3
secretion studies although amides 8 and 9 displayed weak
activity. Treatment of the amide 8 with Lawesson’s
I and I ).
1
2
9
reagent gave the thioamide 10 (Scheme 1). This product
R
R
appeared to inhibit insulin secretion in response to glucose
N
X
by a mechanism that was unrelated to the I -receptor and
3
O
O
HN
HN
Y
was not studied further.
1
2
(R=Et)(efaroxan)
(R=H)(RX801080)
3
The urea 13 was prepared from the amide 8 in modest
yield by treatment with (diacetoxyiodo)benzene (DAIB)
in hot toluene. We believe that this product is formed via
oxidative rearrangement of the amide 8 to the isocyanate
Figure 1 Structure of efaroxan (1) and related analogues 2 and 3
1
7, which adds to a second molecule of the amide 8 to give
Insulin secretagogue activity mediated by imidazoline ag-
onists is known to be associated with closure of ATP-sen-
sitive potassium (KATP) channels, leading to membrane
the acylurea 18 (Scheme 2). The intermediate 18 then re-
acts with the acetic acid formed in the first step to give the
urea 13. Although we have not detected the intermediate
2
+
depolarisation and Ca influx, but the relationship be-
tween binding site and channel has not yet been estab-
1
8, a similar oxidation of furan-2-carboxamide gave the
1
0
4
corresponding acylurea as the major product (57%). The
urea 13 retained weak I -agonism in insulin secretion
studies but was not sufficiently active to merit further
evaluation.
lished. Indeed, recent evidence suggests that the I3
3
receptor may also control secretary events at a site distal
5
to the channel. Work on the characterisation of the bind-
ing site(s) is limited by the lack of sufficiently potent
ligands. We have therefore initiated an investigation of The amides 8 and 9 were converted into the corresponding
novel compounds related to efaroxan (1) with the objec- nitriles 11 and 12 using phosphorus oxychloride in hot py-
ridine. Treatment of the nitrile 11 with methanolic sodium
methoxide to generate the imidate followed by aminoacet-
Synthesis 2001, No. 10, 30 07 2001. Article Identifier:
aldehyde diethylacetal [H NCH CH(OEt) ] and acetic
1
437-210X,E;2001,0,10,1546,1550,ftx,en;E02501SS.pdf.
Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
2
2
2
11
©
acid at reflux temperature gave the imidazole 14

PAPER
Preparation of the I Imidazoline Receptor Antagonist KU14R
1547
3
R
i, SOCl2 / toluene
ii, R R NH /MeOH
R
no signals are observed for the imidazole CH carbon at-
oms and we also attribute this to broadening as a result of
tautomerism. All other aspects of the C NMR spectrum
are in agreement with the structure 14. The mass spectrum
shows a strong molecular ion [m/z = 214 (40%)] with the
base peak at m/z = 185 corresponding to loss of the ethyl
substituent.
1
2
O
CO2H
70-80%
O
O
13
NR R2
1
2
1
4
5
(R=Et)
(R=H)
6 (R=R =Et, R =H)
1
2
7 (R=Et, R =R =Me)
i, SOCl2 / toluene
ii, aq.NH3 /dioxane
8
0-85%
We have previously described the preparation of the benz-
imidazole analogue 20 from the N-phenylamidine 19
(Figure 2) as part of a study of the oxidation of amidines
by I(III) reagents.12 In contrast to the imidazole 14, the
R
O
Et
S
Lawesson's reagent
66%
O
O
NH2
NH2
8
9
(R=Et)
(R=H)
benzimidazole 20 showed no activity at the I receptor,
10
3
possibly due to steric hindrance at the receptor. Like the
amides 6 and 7 and the thioamide 10, the amidine 19 was
also biologically inactive in the imidazoline receptor as-
say.
PhI(OAc)2 / toluene/110 °C
8.5%
7
5-80% POCl3 / pyridine
1
R
Et
CN
O
NHCONH2
O
Et
Et
NPh
NH2
N
1
1
1 (R=Et)
2 (R=H)
13
O
O
HN
AlCl3 / NaN3 / THF
90%
i, MeONa / MeOH
ii, NH2CH2CH(OEt)2 /MeCO2H
19
20
80%
Figure 2
Et
R
N
N
N
N
The imidazoline 2 (Figure 1) (RX801080)13 is the only
O
O
HN
HN
other compound known to be an antagonist [EC 40 M]
5
0
16
1
4 (R=Et)(KU14R)
5 (R=H)
of the I receptor. Since substituent contributions to bio-
3
1
logical activity at different positions of a molecule are of-
ten found to be additive (the Free-Wilson model),14 we
also prepared and evaluated the imidazoline derivative 15
which has the structural features of both antagonists.
Thus, treatment of the nitrile 12 with aminoacetaldehyde
diethylacetal gave the imidazole 15 in good yield. Al-
Scheme 1
(
KU14R) in good yield. The structure of compound 14 is
fully supported by its spectroscopic properties and ele-
mental analysis. In the H NMR spectrum, the benzylic
protons are non-equivalent and appear as doublets
1
though this product is an I -antagonist it did not show en-
3
hanced activity over KU14R.
(
J = 15.9 Hz) centered at = 3.39 and 3.77. Similarly,
Finally, we have prepared the tetrazole derivative 16 for
direct comparison with the isoconjugate imidazole 14.
Treatment of the nitrile 11 with a mixture of aluminium
the methylene protons of the ethyl substituent are non-
equivalent and appear as a multiplet at = 2.15. The im-
idazole CH protons appear as two very broad singlets, due
to imidazole tautomerism, among the other aromatic pro-
15
chloride and sodium azide gave the tetrazole 16 in high
yield. The assigned structure was fully supported by ele-
mental analysis and spectroscopic properties, which were
very similar to those of compound 14. The mass spectrum
shows a molecular ion and a fragment ion corresponding
1
3
tons in the range = 6.8–7.3. In the C NMR spectrum
Et
to loss of HN . In contrast to the imidazole 14, the more
3
DAIB
8
(R = Et)
acidic tetrazole 16 had no properties of biological interest.
We conclude from these studies that the binding require-
ments for the imidazoline fragment of efaroxan (1) and
the imidazole fragment of KU14 R are highly specific and
closely related structures show complete loss of activity.
All compounds described in this study were prepared and
tested as racemates. Products of special interest, e.g.
KU14R, have been resolved and the properties of enantio-
mers will be described elsewhere.
O
N C O
AcOH
1
7
8
(R = Et)
Et
O
O
H+
8.5%
13
O
1
N
H
N
H
Et
O
1
The H NMR spectra were recorded on a Bruker Advance DPX300
18
NMR spectrometer; IR spectra on a Perkin-Elmer Paragon 1000
FT-IR spectrophotometer, mass spectra on a Hitachi-Perkin-Elmer
Scheme 2
Synthesis 2001, No. 10, 1546–1550 ISSN 0039-7881 © Thieme Stuttgart · New York

1
548
J. Clews et al.
PAPER
MSI 12 spectrometer and microanalyses on a Perkin-Elmer 240 el-
emental analyzer. Unless otherwise state, IR spectra were measured
as thin films (liquids) or KBr discs (solids) and 300 MHz NMR
J = 16.6 Hz, ArCH H ), 3.89 (1 H, d, J = 16.6 Hz, ArCH H ),
6.81–7.16 (4 H, m, arom H), 7.85 (1 H, br s, CSNH), 8.20 (1 H, br
s, CSNH).
a
b
a
b
spectra in CDCl (tetramethylsilane as internal standard). Only sig-
13
3
C NMR (CDCl /TMS): = 7.98 (q), 34.43 (t), 42.55 (t), 96.84
3
nificant bands for the IR spectra are quoted. Melting points were de-
termined on a Kofler block and are uncorrected. Chromatotron
chromatography was performed on plates prepared using silica gel
(
1
s), 109.54 (d), 121.59 (d), 125.03 (d), 125.73 (s), 128.12 (d),
57.44 (s), 210.35 (s).
+
MS (EI): m/z = 207 (M ), 174 (100%), 163, 146.
6
0 PF254 containing CaSO . Petroleum ether used refers to the frac-
4
tion boiling at 60–80°C.
Anal. Calcd for C H NOS (207.3): C, 63.74; H, 6.32; N, 6.76.
1
1
13
Found: C, 63.52; H, 6.58; N, 6.59.
2
,3-Dihydro-2-ethylbenzo[b]furan-2-carboxamide (8); Typical
Procedure
SOCl (5.37 g, 45 mmol) was added to a suspension of the acid 4
N-(2,3-Dihydro-2-ethylbenzo[b]furan-2-yl)urea (13)
8
2
To a stirred solution of (diacetoxyiodo)benzene (DAIB) (1.68 g, 5.3
mmol) in anhyd toluene (40 mL) heated at 110°C was added drop-
wise a solution of the amide 8 (1.0 g, 3 mmol) in toluene (10 mL).
After stirring (30 min), the solvent was removed and the residue
heated under vacuum (50°C at 0.001 Torr) for 30 min. The residue
was then purified by chromatotron chromatography (EtOAc–petro-
leum ether) and, after recrystallisation from EtOAc, identified as the
urea 13 (0.20 g, 18.5%); colourless crystals; mp 117–118°C.
(4.44 g, 23 mmol) in anhyd toluene (150 mL). The mixture was
heated with stirring at 90–100°C until all the carboxylic acid was in
solution (25 min). The solvent and excess SOCl were then removed
under diminished pressure to give the acid chloride as an oil. The
crude product was dissolved in anhyd dioxane (18 mL) and the so-
lution was added dropwise with stirring to aq ammonia (SG 0.88,
2
2
7.0 mL) at 0°C. After the addition was complete, the mixture was
allowed to warm to r.t. and H O (120 mL) was added. The solid
product was recrystallised from EtOAc–petroleum ether and identi-
fied as the amide 8 (3.70 g, 85%); tiny colourless crystals; mp 96–
9
2
IR (KBr): = 3507, 3361, 3306, 1658, 1607, 1566, 1484, 1463,
–
1
1
355, 1335, 1257, 1230, 942, 872, 761 cm .
1H NMR (DMSO-d
/TMS): = 0.88 (3 H, t, J = 7.4 Hz,
CCH CH ), 1.82 (1 H, m, CH H CH ), 2.03 (1 H, m, CH H CH ),
7°C.
6
2
3
a
b
3
a
b
3
IR (KBr): = 3459, 3192, 2972, 2914, 1637, 1484, 1462, 1438,
1
–
1
3.02 (1 H, d, J = 16.2 Hz, ArCH
a b
H ), 3.55 (1 H, d, J = 16.2 Hz,
327, 1277, 1233, 1145, 1073, 1019, 960, 892, 865, 788, 757 cm .
ArCH H ), 5.60 (2 H, s, NH ), 6.60–7.15 (5 H, m, 4 arom H + NH).
a
b
2
1
H NMR (CDCl /TMS): = 1.00 (2 H, t, J = 7.3 Hz, CH CH ),
3
2
3
MS (EI): m/z = 207 (MH+).
1
.92 (1 H, m, CH H CH ), 2.09 (1 H, m, CH H CH ), 3.16 (1 H, d,
a b 3 a b 3
J = 16.6 Hz, ArCH H ), 3.56 (1 H, d, J = 16.6 Hz, ArCH H ), 6.68
Anal. Calcd for C11H N O (206.2): C, 64.06; H, 6.84; N, 13.58.
14 2 2
a
b
a
b
(
2 H, br s, NH ), 6.81–7.15 (4 H, m, arom H).
Found: C, 64.31; H, 6.97; N, 13.70.
2
1
3
C NMR (CDCl /TMS): = 8.05 (q), 31.43 (t), 39.12 (t), 91.36
3
N-Ethyl-2,3-dihydro-2-ethylbenzo[b]furan-2-carboxamide (6)
Following the method described for compound 8, the title com-
pound was obtained from the carboxylic acid 4 (4.44 g, 23 mmol)
and methanolic ethylamine (2 M); yield: 3.63 g (72%); hygroscopic
plates; mp 38–39°C.
(
1
s), 109.58 (d), 121.39 (d), 125.09 (d), 125.76 (s), 128.14 (d),
58.15 (s), 177.32 (s).
MS (EI): m/z = 191 (M+).
Anal. Calcd for C H NO (191.2): C, 69.09; H, 6.85; N, 7.32.
1
1
13
2
Found: C, 68.97; H, 6.89; N, 7.18.
IR (KBr): = 2974, 1660, 1597, 1526, 1482, 1463, 1240, 959, 870,
–
1
7
50 cm .
2
,3-Dihydrobenzo[b]furan-2-carboxamide (9)
1
H NMR (CDCl /TMS): = 0.97 (3 H, t, J = 7.3 Hz, CCH CH ),
3
2
3
Following the method described for compound 8, the title com-
pound was obtained from the carboxylic acid 5 (7.5 g, 46 mmol);
yield: 6.0 g (80%); colourless platelets from EtOAc; mp 158–
8
1.14 (3 H, t, J = 7.3 Hz, NCH
2
CH
3
), 1.91 (1 H, m, CCH
a
H
b
CH
3
),
2
3
.09 (1 H, m, CCH H CH ), 3.15 (1 H, d, J = 16.1 Hz, ArCH H ),
a
b
3
a
b
.20 (1 H, m, NCH H CH ), 3.37 (1 H, m, NCH H CH ), 3.55 (1 H,
a
b
3
a
b
3
1
59°C.
d, J = 16.1 Hz, ArCH H ), 6.74 (1 H, br s, CONH), 6.82–7.16 (4 H,
a
b
IR (KBr): = 3410, 3204, 1635, 1484, 1465, 1228, 1107, 1010,
m, arom H).
–1
8
73, 745 cm .
1
3
C NMR (CDCl /TMS): = 8.08 (q), 14.83 (q), 31.69 (t), 34.07
3
1
H NMR (CDCl /TMS): = 3.45 (1 H, m, CH H ), 3.56 (1 H, m,
3
a
b
(t), 39.24 (t), 91.47 (s), 109.55 (d), 121.29 (d), 125.11 (d), 125.89
(s), 128.03 (d), 158.09 (s), 173.19 (s).
CH H ), 5.12 (1 H, dd, J = 6.6, 10.8 Hz, CHCH ), 6.2 (1 H, br s,
a
b
2
CONH), 6.6 (1 H, br s, CONH), 6.85–7.25 (4 H, m, arom H).
+
MS (EI): m/z = 219 (M ), 190, 174, 131, 119, 91 (100%).
+
MS (EI): m/z = 163 (M ), 146, 119, 91 (100%).
Anal. Calcd for C H NO (219.3): C, 71.21; H, 7.81; N, 6.39.
1
3
17
2
Anal. Calcd for C H NO (163.2): C, 66.25; H, 5.56; N, 8.58.
9
9
2
Found: C, 71.29; H, 7.77; N, 6.21.
Found: C, 66.31; H, 5.47; N, 8.29.
N,N-Dimethyl-2,3-dihydro-2-ethylbenzo[b]furan-2-
carboxamide (7)
Following the method described for compound 8, the title com-
pound was obtained from the carboxylic acid 4 (4.44 g, 23 mmol)
and methanolic dimethylamine (2 M); yield: 3.93 g (78%); pale
cream crystals; mp 51–52°C.
2
,3-Dihydro-2-ethylbenzo[b]furan-2-thiocarboxamide (10)
A mixture of the amide 8 (1.91 g, 10 mmol) and Lawesson’s reagent
4.40 g, 10 mmol) in toluene (75 mL) was heated under reflux (5 h).
(
The solvent was removed under vacuum and the residue purified by
chromatotron chromatography (EtOAc–petroleum ether). Recrys-
tallisation from EtOAc–petroleum ether gave the thioamide 10
IR (KBr): = 1625, 1483, 1397, 1242, 1171, 1088, 1014, 957, 871,
(1.37 g, 66%); fine colourless needles; mp 135–137°C.
–
1
7
49, 671 cm .
IR (KBr): = 3378, 3261, 3155, 2971, 1618, 1482, 1446, 1311,
1
H NMR (CDCl /TMS): = 0.96 (3 H, t, J = 7.3 Hz, CH CH ),
3
2
3
1
6
1
233, 1141, 1115, 1093, 1064, 1023, 962, 893, 872, 850, 752, 688,
–
1
1.97 (1 H, m, CH H CH ), 2.06 (1 H, m, CH H CH ), 2.97 (3 H, s,
a b 3 a b 3
64 cm .
NCH ), 3.12 (1 H, d, J = 16.6 Hz, ArCH H ), 3.27 (3 H, s, NCH ),
3
a
b
3
H NMR (CDCl /TMS): = 0.99 (2 H, t, J = 7.3 Hz, CH CH ),
3
2
3
3.93 (1 H, d, J = 16.6 Hz, ArCH H ), 6.77–7.17 (4 H, m, arom H).
a b
2
.10 (1 H, m, CH H CH ), 2.34 (1 H, m, CH H CH ), 3.36 (1 H, d,
a b 3 a b 3
Synthesis 2001, No. 10, 1546–1550 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Preparation of the I Imidazoline Receptor Antagonist KU14R
1549
3
1
3
+
C NMR (CDCl /TMS):
= 8.02 (q), 31.66 (t), 37.70 (q),
MS (EI): m/z = 214 (M ), 213, 197, 185 (100%), 169, 156, 131.
3
3
1
8.10(q), 39.08 (t), 93.03 (s), 109.10 (d), 120.90 (d), 124.72 (d),
26.07 (s), 127.84 (d), 158.24 (s), 171.75 (s).
Anal. Calcd for C H N O (214.3): C, 72.87; H, 6.59; N, 13.07.
Found: C, 72.60; H, 6.74; N, 13.26.
1
3
14
2
+
MS (EI): m/z = 219 (M ), 190, 175, 146, 131, 119, 91 (100%).
2
-(2,3-Dihydrobenzo[b]furan-2-yl)-1H-imidazole (15)
Anal. Calcd for C H NO (219.3): C, 71.21; H, 7.81; N, 6.39.
Found: C, 70.99; H, 8.05; N, 6.21.
1
3
17
2
Following the method described for compound 14, the title com-
pound was obtained from the nitrile 12 (1.67 g. 11.5 mmol); yield:
1
1
.7 g (79%); colourless crystals from EtOAc–petroleum ether; mp
95–196°C.
Dihydro-2-ethylbenzo[b]furan-2-carbonitrile (11)
A solution of the amide 8 (1.44 g, 7.5 mmol) in anhyd pyridine (30
mL) was cooled to 0°C. POCl (3.63 g, 7.8 mmol) was added with
IR (KBr): = 2300–3850 (br), 1597, 1480, 1459, 1406, 1234,
1165, 1107, 1016, 997, 950, 926, 856, 770, 750 cm .
3
–
1
stirring and the resulting solution was heated under reflux (2.5 h).
The solvent was then removed under vacuum and the residue parti-
tioned between dil. HCl (60 mL) and CH Cl (3 60 mL). The com-
1
H NMR (acetone-d /TMS): = 3.55 (1 H, m, CH H ), 3.75 (1 H,
6
a
b
2
2
m, CH H ), 5.81 (1 H, dd, J = 7.7, 9.5 Hz, CHCH ), 6.70–7.20 (6
a
b
2
bined organic extracts were washed with brine (60 mL), dried
Na SO ) and evaporated to give the nitrile 11 as a yellow oil (1.09
H, m, arom H), 11.51 (1 H, br s, NH).
(
2
4
+
MS (EI): m/z = 186 (M ), 169 (100%), 156, 128, 118.
g, 76%) that was shown to be pure by NMR and was used without
further purification.
Anal. Calcd for C H N O (186.2): C, 70.95; H, 5.41; N, 15.04.
1
1
10
2
1
Found: C, 70.69; H, 5.42; N, 15.18.
H NMR (CDCl /TMS): = 1.22 (3 H, t, J = 7.4 Hz, CH CH ),
3
2
3
2
.09 (2 H, m, CH CH ), 3.30 (1 H, d, J = 15.9 Hz, ArCH H ), 3.61
2
3
a
b
5
-(2,3-Dihydro-2-ethylbenzo[b]furan-2-yl)-1H-tetrazole (16)
(
1 H, d, J = 15.9 Hz, ArCH H ), 6.80–7.21 (4 H, m, arom H).
a b
Anhyd AlCl (2.84 g, 22 mmol) was carefully added to cold, anhyd
THF (35 mL). When all the material had dissolved, NaN (4.14 g,
MS (EI): m/z = 173 (M+).
3
3
6
1
4 mmol) was added with vigorous stirring followed by the nitrile
1 (1.2 g, 7 mmol). The mixture was then heated under reflux (24
Dihydrobenzo[b]furan-2-carbonitrile (12)
A solution of the amide 9 (5.5 g, 337 mmol) in anhyd pyridine was
h) and poured onto a mixture of ice (75 g) and concd HCl (20 mL).
The product was extracted into Et O and the ethereal solution dried
cooled to 0°C and POCl (16.5 g) was added with stirring. The so-
3
2
lution was then heated under reflux (2.5 h). The solvent was re-
moved under reduced pressure and the residue partitioned between
CH Cl and dil. HCl. The organic phase was washed with 10% aq
(
MgSO ). Evaporation gave the crude product (1.75 g) as a yellow
4
oil that was purified by chromatotron chromatography (EtOAc–pe-
troleum ether and identified as the tetrazole 16 (1.35 g, 90%); co-
lourless crystals; mp 96–97°C.
2
2
NaCl solution, dried (MgSO ) and evaporated to give the nitrile 12
4
as a yellow oil (4.0 g, 82%) that was shown to be pure by NMR and
was used without further purification.
IR (KBr): = 2600–3100 (br), 1597, 1545, 1481, 1464, 1441,
1
1
1
423, 1410, 1382, 1326, 1300, 1278, 1236, 1188, 1151, 1121, 1083,
IR (KBr): = 2220 (w), 1733, 1596, 1480, 1463, 1325, 1240, 1224,
–1
051, 1016, 984, 951, 874, 754 cm .
–
1
1
154, 1095, 1002, 967, 852, 753 cm .
H NMR (CDCl /TMS): = 0.95 (3 H, t, J = 7.3 Hz, CH CH ),
1
3
2
3
H NMR (CDCl /TMS): = 3.35–3.60 (2 H, m, ArCH CH), 5.25
3
2
2
.25 (2 H, dq, CH CH ), 3.54 (1 H, d, J = 16.1 Hz, CH H ), 3.73 (1
2
3
a
b
(
1 H, dd, J = 5.7, 9.8 Hz, ArCH CH), 6.80–7.20 (4 H, m, arom H).
2
H, d, J = 16.1 Hz, CH H ), 6.77–7.15 (4 H, m, arom H), 13.3 (1 H,
v br s, NH).
a
b
1
3
C NMR (CDCl /TMS): = 35.42 (t), 68.01 (d), 110.23 (d),
3
1
18.15 (s), 122.29 (d), 123.56 (s), 124.98 (d), 128.93 (d), 157.70 (s).
+
MS (EI): m/z = 216 (M ), 173, 146, 43 (100%).
+
MS (EI): m/z = 145 (100%, M ), 118, 90.
Anal. Calcd for C H N O (216.2): C, 61.10; H, 5.59; N, 25.91.
1
1
12
4
Found: C, 61.30; H, 5.65; N, 26.17.
2
-(2,3-Dihydro-2-ethylbenzo[b]furan-2-yl)-1H-imidazole
(
KU14R) (14); Typical Procedure
A solution of NaOMe (1 M in MeOH, 3.0 mL) was added with stir-
ring to a solution of the nitrile 11 (2.0 g, 11.6 mmol) in MeOH (40
mL). After stirring at r.t. (18 h), the solution was cooled to 0 ° C and
aminoacetaldehyde diethylacetal (1.54 g, 11.6 mmol) and AcOH
References
(
1) (a) Molderings, G. J. Drugs Future 1997, 22, 757.
b) Regunathan, S.; Reis, D. J. Annu. Rev. Pharmacol.
Toxicol. 1996, 36, 511.
(
(
(
1.4 g, 23.0 mmol) were added and the mixture heated under reflux
3 h).13 After cooling to r.t., 5 M HCl (9.0 mL) was added and the
(2) (a) Eglen, R. M.; Hudson, A. L.; Kendall, D. A.; Nutt, D. J.;
Morgan, N. G.; Wilson, V. G.; Dillon, M. P. Trends
mixture boiled under reflux (30 min.). H O (100 mL) was added to
2
Pharmacol. Sci. 1998, 19, 381. (b) Chem. Abstr. 1998, 129,
the cooled mixture, which was then evaporated to dryness under re-
duced pressure. The residue was taken up in water, basified with
NaOH solution and extracted with CH Cl . The organic phase was
2
97851.
3) (a) Morgan, N. G. Exp. Opin. Invest. Drugs 1999, 8, 575.
b) Morgan, N. G.; Chan, S. L. F.; Mourtada, M.; Monks, L.
K.; Ramsden, C. A. Ann. New York Acad. Sci. 1999, 881,
17.
(
(
2
2
(
dried (Na SO ) and evaporated to give a buff solid that was recrys-
2
4
tallised from EtOAc–petroleum ether and identified as compound
4, (2.01 g, 81%); colourless needles; mp 136–136.5°C.
2
1
4) Monks, L. K.; Cosgrove, K. E.; Dunne, M. J.; Ramsden, C.
IR (KBr): = 2600–3100 (br), 1597, 1550, 1485, 1461, 1436,
A.; Morgan, N. G.; Chan, S. L. F. FEBS Letters 1999, 447,
–
1
1
384, 1330, 1241, 1190, 1098, 1016, 950, 874, 750, 735 cm .
61.
1
H NMR (CDCl /TMS): = 0.91 (3 H, t, J = 7.3 Hz, CH CH ),
(5) (a) Chan, S. L. F.; Mourtada, M.; Morgan, N. G. Diabetes
2001, 50, 340. (b) Zaitsev, S. V.; Efanov, A. M.; Efanova, I.
B.; Larsson, O.; Ostenson, C.-G.; Gold, G.; Berggren, P.-O.;
Efendic, S. Diabetes 1996, 45, 1610. (c) Morgan, N. G.;
Chan, S. L. F. Curr. Pharmaceut. Design 2001, in press.
3
2
3
2
.15 (2 H, m, CH CH ), 3.39 (1 H, d, J = 15.9 Hz, CH H ), 3.77 (1
2
3
a
b
H, d, J = 15.9 Hz, CH H ), 6.79–7.26 (6 H, m, arom H), 9.87 (1 H,
a
b
br s, NH).
1
3
C NMR (CDCl /TMS): = 8.3 (q), 34.0 (t), 40.8 (t), 89.2 (s),
3
1
09.5 (d), 121.0 (d), 125.2 (d), 126.5 (s), 127.7 (d), 150.9 (s), 158.5
(s).
Synthesis 2001, No. 10, 1546–1550 ISSN 0039-7881 © Thieme Stuttgart · New York

1
550
J. Clews et al.
PAPER
(
6) (a) Chan, S. L. F.; Pallett, A. L.; Clews, J.; Ramsden, C. A.;
(11) Lawson, A. J. Chem. Soc. 1957, 4225.
Morgan, N. G. Eur. J. Pharmacol. 1997, 323, 241.
(12) Ramsden, C. A.; Rose, H. L. J. Chem. Soc., Perkin Trans. 1
1997, 2319.
(
b) Chan, S. L. F.; Atlas, D.; James, R. F. L.; Morgan, N. G.
Br. J. Pharmacol. 1997, 120, 926.
(13) Brown, C. A.; Chan, S. L. F.; Stillings, M. R.; Smith, S. A.;
Morgan, N. G. Br. J. Pharmacol. 1993, 110, 1017.
(14) Kubinyi, H. In Comprehensive Medicinal Chemistry, Vol. 4;
Ramsden, C. A., Ed.; Pergamon Press: Oxford, 1990, 589.
(15) Ford, R. E.; Knowles, P.; Lunt, E.; Marshall, S. M.; Penrose,
A. J.; Ramsden, C. A.; Summers, A. J. H.; Walker, J. L.;
Wright, D. E. J. Med. Chem. 1986, 29, 538.
(
7) Chan, S. L. F.; Pallett, A. L.; Clews, J.; Ramsden, C. A.;
Chapman, J. C.; Kane, C.; Dunne, M. J.; Morgan, N. G. Eur.
J. Pharmacol. 1998, 355, 67.
8) Edwards, C. R.; Readhead, M. J.; Tweddle, N. J. J.
Heterocycl. Chem. 1987, 24, 495.
(
(
9) Cava, M. P.; Levinson, M. I. Tetrahedron 1985, 41, 5061.
(10) Clews, J.; Ramsden, C. A. unpublished work.
Synthesis 2001, No. 10, 1546–1550 ISSN 0039-7881 © Thieme Stuttgart · New York