Synthesis of New 4,5,6,7-Tetrahydro-3H-imidazo[4,5-c]pyridine Derivatives

Article abstract of DOI:10.1002/jhet.5570400528

The synthesis of new ligands for the H₃ histamine receptor is described. These new compounds are spinacine derivatives obtained by alkylation or Michael reaction at C6 position.

Full text of DOI:10.1002/jhet.5570400528

Sep-Oct 2003
917
Synthesis of New 4,5,6,7-Tetrahydro-
3H-imidazo[4,5-c]pyridine Derivatives
Miguel F. Braña*, Cristina Guisado and Francisca Sanz
Facultad de Ciencias Experimentales y de la Salud.
Universidad San Pablo CEU, Urb. Montepríncipe, 28668 Boadilla del Monte, Madrid, and Universidad de
Salamanca. Spain
Received April 28, 2003
The synthesis of new ligands for the H histamine receptor is described. These new compounds are
3
spinacine derivatives obtained by alkylation or Michael reaction at C6 position.
J. Heterocyclic Chem., 40, 917 (2003).
The H histamine receptor was demonstrated to be
3
located presynaptically on histaminergic neurons in the
central nervous system (CNS) where it regulates histamine
synthesis and release as autoreceptor [1,2]. Inhibition of
this negative feedback mechanism by H receptor antago-
3
nists, thus, increases concentration of the histamine
released [3].
Moreover, H receptors function as heteroreceptors on
3
nonhistaminergic neurons in the brain and the periphery,
inhibiting the release of neuropeptides [4] and several
other neurotransmitters such as acetylcholine, dopamine,
serotonin and noradrenaline [5]. In radiolabeling studies,
the highest density of H receptors was found in distinct
3
areas of the CNS [6], and it is suggested that the potential
therapeutic role of H receptor antagonists may be the
3
treatment of various neurological and psychiatric diseases,
e.g. epilepsy, narcolepsy, schizophrenia, or dementia [7].
New pharmacological tools are highly recommended to
clarify these therapeutic indications.

918
M. F. Braña, C. Guisado and F. Sanz
Vol. 40
In this work we describe the synthesis of 4,5,6,7-tetrahy-
dro-3H-imidazo[4,5-c]pyridine derivatives as new ligands
The synthetic route for preparing the target compounds
IIa-b is portrayed in Scheme 2. The diastereoselective
Michael addition of nitrovinyl compounds 5a-b to the eno-
late of 2 afforded 6a (52%) and 6b (93%). The Michael
acceptor 5b was synthesized by ultrasound promoted
Knovenagel condensation of its correspondent aldehyde in
moderate yield (52%) [13] (Scheme 3). The relative
stereochemistry of the compounds 6a-b was determined
by single–crystal X-rays analysis (Figures 3 and 4) of their
cyclic derivatives 9a-b (Scheme 4). The hydrogenation of
6a-b, with cyclohexene and the Pd-C (10%) catalyst [12],
provided 7a-b in good yield. Reduction of the amino
group under 40 psi of hydrogen in presence of palladium,
followed by acidic hydrolysis of the ester group and the
carbamate moiety rendered IIa (90%) and IIb (92%).
for the H receptor of histamine. The development of rigid
3
histamine analogues had contributed to the determination
of the H receptor pharmacophore, e.g. the cyclopropylhis-
3
tamine [8] or the immepip [9] (Figure 1). Therefore, as
part of our medicinal chemistry studies directed towards
the preparation of new H receptor ligands, we have
3
selected spinacine [10], as a template for the development
of such analogues, as it can be looked at as conformation-
ally restricted analogue of histidine (Figure 1). Several
substituents have been introduced at the C6 position in
order to determine the influence on the biological activi-
ties of these derivatives I and IIa-b (Figure 2).
The pathway outlined in Scheme 1 yielded the desired
histamine analogue I. N -benzyl-spinacine methyl ester 1
im
was obtained according to literature procedures [11].
Protection of the amino group was achieved by reaction of
1 with ethyl chloroformate (70% yield). The only produc-
tive reaction conditions for the alkylation of 2 were deter-
mined to be generation of the carbanion of 2 with
NaHMDS in THF at –78 °C, followed by reaction with 2
equiv of methyl iodide at –78 °C (97% yield). The hydro-
genation of the N-benzyl group in the racemic ester 3 [12],
followed by acidic hydrolysis of the carbamate moiety and
the ester group, furnished I (73% two steps yield).

Sep-Oct 2003
Synthesis of New 4,5,6,7-Tetrahydro-3H-imidazo[4,5-c]pyridine Derivatives
919
states in this reaction explains the total diastereoselectivity
observed.
The affinity of new compounds for the histamine H
3
receptor was assessed by the study of the inhibition of the
3
3
specific binding of [ H] (R)-α-methylhistamine ([ H]
RMHA) in rat brain membranes [14]. All the compounds
tested showed less affinity than (R)-α-methylhistamine,
used as the reference compound (data not shown).
EXPERIMENTAL
Melting points were determined on a Büchi 530 apparatus and
were uncorrected. IR spectra were recorded on a Perkin Elmer
1330 infrared spectrophotometer as potassium bromide pellets.
NMR spectra were determined on a Bruker AM-300 instrument.
1
13
H and C NMR spectra were recorded at 300 and 75.43 MHz,
Figure 3. ORTEP drawingo or compound 9a.
Figure 4. ORTEP drawingo or compound 9b.
Functionalization of spinacine at C6 position had not
been described yet, so we have established the reaction
conditions for alkylations and Michael reactions on this
structure. Michael reactions are totally diastereoselective
for the Michael acceptors we have used. Although a deeper
study is required, it seems probable that an important dif-
ference in stability between the two possible transition
respectively. Chemical shifts for hydrogen and carbon were
reported in ppm (δ) relative to tetramethylsilane, using DMSO-
d , D O, CD OD and CDCl as solvents. Merck silica gel (230-
400 mesh) was used for flash chromatography. Elemental analy-
ses were performed in the UCM Microanalysis Service (Facultad
de Farmacia, Universidad Complutense de Madrid, Spain) and
agreed with theoretical values to within ±0.4%. Single crystals of
compounds 9a-b suitable for X-ray diffraction were selected
directly from the analytical samples.
6
2
3
3
Methyl (6S)-3-Benzyl-5-ethyloxycarbonyl-4,5,6,7-tetrahydro-
3H-imidazo[4,5-c]pyridin-6-carboxylate (2).
A solution of Na CO 2 M (67.7 ml) and ethyl chloroformate
2
3
(11.8 ml, 123.18 mmol) were added dropwise to a stirred solution
of N -benzyl-spinacine methyl ester 1 (16.71 g, 61.59 mmol) in
im
absolute EtOH (100 ml) at 0 °C. The mixture was stirred at room
temperature for 12 h. After removal of the solvent under reduced
pressure, the residual semisolid was purified by column chro-
matography on silica using CHCl /MeOH (250:1→50:1) as elu-
3
ent to give a homogeneous residue, which was crystallized from
EtOAc to yield the ester 2 (14.70 g, 70%) as a white solid, m.p.

920
M. F. Braña, C. Guisado and F. Sanz
Vol. 40
-1
1
59.4 (COOCH ), 62.0 (CHCOOCH ), 124.4 (Im-C5), 124.8 (Im-
102-104 °C); IR ν cm : 1740, 1720, 1490; H-NMR (DMSO-
d ): δ 1.16 (t, 3H, COOCH CH , J = 7.3 Hz.), 2.88-2.94 (m, 1H,
3
3
C4), 133.9 (Im-C2), 156.0 (NCOOCH CH ), 172.5 (COOCH );
2
3
3
6
2
3
+
MS (EI): m/z 267 (M , 32), 252 (3), 208 (79), 194 (21), 134 (41),
1/2 ImCH CH), 3.03 (d, 1H, 1/2 ImCH CH, J = 15.8 Hz.), 3.55
2
2
119 (24), 94 (100).
(s, 3H, COOCH ), 3.96 (d, 1H, 1/2 ImCH N, J = 15.2 Hz.), 4.07
3
2
(q, 2H, COOCH CH , J = 7.3Hz.), 4.48 (d, 1H, 1/2 ImCH N, J =
2
3
2
(±)-6-Methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-6-
carboxylic Acid (I).
15.2 Hz.), 5.17 (br s, 2H, NCH Ph), 5.23 (d, 1H, CHCOOCH , J
2
3
= 6.1 Hz.), 7.08 (d, 2H, Ar, J = 7.3 Hz.), 7.30-7.39 (m, 3H, Ar),
13
A solution of 4 (0.96 g, 3.59 mmol) in HCl 6 N (50 ml, 300.00
mmol) was stirred at reflux temperature for 48 h. After removal
of the solvent under reduced pressure, the residue was purified by
7.69 (s, 1H, Im-H2); C-NMR (CDCl ): δ 14.5 (COOCH CH ),
3
2
3
26.5 (ImCH CH), 39.0 (ImCH N), 48.9 (NCH Ph), 52.4
2
2
2
(COOCH CH ), 53.2 (COOCH ), 62.1 (CHCOOCH ), 121.7
2
3
3
3
recrystallization from EtOH/Et O to give I (0.69 g, 76%) as a
(Im-C5), 126.9 (Im-C4), 128.3 (Ar), 129.0 (Ar), 132.5 (Ar),
133.0 (Ar), 135.2 (Ar), 137.0 (Im-C2), 156.4 (NCOOCH CH ),
2
-1
white solid, m.p. 249-250 °C; IR ν cm : 3400, 2900-2700, 1740;
2
3
1
+
H-NMR (D O): δ 1.45 (s, 3H, CCH ), 2.94 (d, 1H, 1/2 ImCH C,
171.6 (COOCH ); MS (EI): m/z 343 (M , 17), 284 (17), 270 (32),
2 3 2
3
J = 17.0 Hz.), 3.23 (d, 1H, 1/2 ImCH C, J = 17.0 Hz.), 4.23 (d,
252 (27), 120 (7), 91 (100).
2
1H, 1/2 ImCH N, J = 15.9 Hz.), 4.40 (d, 1H, 1/2 ImCH N, J =
2
2
Methyl (±)-3-Benzyl-5-ethyloxycarbonyl-6-methyl-4,5,6,7-
tetrahydro-3H-imidazo[4,5-c]pyridin-6-carboxylate (3).
13
15.9 Hz.), 8.51 (s, 1H, Im-H2); C-NMR (D O): δ 22.8 (CCH ),
2
3
29.9 (ImCH CH), 39.1 (ImCH N), 63.7 (CHCOOH), 121.7 (Im-
2
2
C5), 126.4 (Im-C4), 137.6 (Im-C2), 175.4 (COOH); MS (ESI):
m/z 182 [M+H] .
To a 1 M solution of sodium hexamethyldisilazide in THF (3.2
ml, 3.20 mmol) stirred at –78 °C under argon atmosphere was
added a solution of ester 2 (1.00 g, 2.90 mmol) in dry THF (10
ml). The mixture was stirred at –78 °C for 1 h. Methyl iodide (0.4
ml, 5.80 mmol) disolved in dry THF (5 ml) was added at –78 °C,
and the mixture was then stirred for 12 h at room temperature.
The reaction mixture was quenched with saturated solution of
ammonium chloride and extracted with EtOAc. The combined
+
Anal. Calcd. for C H N O •2HCl•0.25H O: C, 37.15; H,
8
11
3
2
2
5.22; N, 16.25. Found: C, 37.14; H, 5.02; N, 16.64.
Methyl (6R*,1'S*)-3-Benzyl-5-ethyloxycarbonyl-6-(2'-
nitroethyl-1'-phenyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]-
pyridin-6-carboxylate (6a).
To a 1 M solution of sodium hexamethyldisilazide in THF
(8.0 ml, 8.02 mmol) stirred at –78 °C under argon atmosphere
was added a solution of ester 2 (2.50 g, 7.29 mmol) in dry
THF (30 ml). The mixture was stirred at –78 °C for 1 h. The
trans-β-nitrostyrene 5a (2.17 g, 14.58 mmol) dissolved in dry
THF (30 ml) was added at –78 °C, and the mixture was then
stirred for 12 h at room temperature. The reaction mixture was
quenched with saturated solution of ammonium chloride and
extracted with EtOAc. The combined organic phases were
dried over Na SO , filtered and evaporated to dryness. The
organic phases were dried over Na SO , filtered and evaporated
2
4
to dryness. The residual semisolid was purified by column chro-
matography on silica using CHCl /MeOH (120:1) as eluent to
3
give a homogeneous residue which was crystallized from CHCl
3
to yield the ester 3 (1.01 g, 97%) as a white solid, m.p. 106-108
-1
1
°C; IR ν cm : 1730, 1690. H-NMR (CDCl ): δ 1.09 (t, 3H,
3
COOCH CH , J = 7.1 Hz.), 1.33 (s, 3H, CCH ), 2.67 (d, 1H, 1/2
2
3
3
ImCH C, J = 15.9 Hz.), 3.26 (d, 1H, 1/2 ImCH C, J = 15.9 Hz.),
2
2
3.69 (s, 3H, COOCH ), 3.82 (d, 1H, 1/2 ImCH N, J = 15.9 Hz.),
3
2
3.96-4.00 (m, 2H, COOCH CH ), 4.61 (d, 1H, 1/2 ImCH N, J =
2
4
2
3
2
residual semisolid was purified by column chromatography on
15.9 Hz.), 4.98 (s, 2H, NCH Ph), 7.02 (d, 2H, Ar, J = 6.6 Hz.),
2
13
silica using CHCl /MeOH (60:1) as eluent to give a homoge-
7.27-7.29 (m, 3H, Ar), 7.43 (s, 1H, Im-H2); C-NMR (CDCl ):
3
3
neous residue which was crystallized from CHCl /MeOH to
δ 13.4 (COOCH CH ), 20.7 (CCH ), 31.6 (ImCH CH), 38.4
3
2
3
3
2
yield the ester 6a (1.87 g, 52%) as a white solid, m.p. 68-70
(ImCH N), 48.2 (NCH Ph), 51.4 (COOCH CH ), 59.7
2
2
2
3
-1
1
°C; IR ν cm : 1730, 1700, 1540; H-NMR (CDCl ): δ 1.12 (t,
(COOCH ), 61.2 (CHCOOCH ), 120.8 (Im-C5), 126.0 (Im-C4),
3
3
3
3H, COOCH CH , J = 7.1 Hz.), 2.69 (d, 1H, 1/2 ImCH C, J =
127.4 (Ar), 128.2 (Ar), 133.3 (Ar), 134.9 (Ar), 136.5 (Im-C2),
2
3
2
17.0 Hz.), 3.21 (d, 1H, 1/2 ImCH C, J = 17.0 Hz.), 3.71 (s,
155.6 (NCOOCH CH ), 172.9 (COOCH ); MS (ESI): m/z 358
[M+H] .
2
2
3
3
+
3H, COOCH ), 3.98-4.07 (m, 4H, 1/2 ImCH N and
3
2
COOCH CH and CHPh), 4.88 (d, 1H, 1/2 ImCH N, J = 16.5
2
3
2
Methyl (±)-5-Ethyloxycarbonyl-6-methyl-4,5,6,7-tetrahydro-
3H-imidazo[4,5-c]pyridin-6-carboxylate (4).
Hz.), 4.99-5.08 (m, 3H, NCH Ph and 1/2 CH NO ), 5.19 (dd,
2
2
2
1H, 1/2 CH NO , J = 13.7 Hz., J = 11.0 Hz.), 6.89-6.92 (m,
2
2
2H, Ar), 7.14 (d, 2H, Ar, J = 7.1 Hz.), 7.26-7.40 (m, 6H, Ar),
To a stirred suspension of the ester 3 (1.40 g, 3.92 mmol) and
10% Pd-C (700 mg) in absolute EtOH (30 ml), cyclohexene (31.8
ml, 313.60 mmol) was added at reflux temperature. The resulting
reaction mixture was stirred for 24 h. The catalyst was removed
by filtration through a celite pad and washed with methanol. The
filtrate was evaporated under reduced pressure. The residue was
purified by recrystallization from EtOAc to give the ester 4 (1.01
13
7.58 (s, 1H, Im-H2);
C-NMR (CDCl ): δ 14.1
3
(COOCH CH ), 27.7 (ImCH CH), 39.4 (ImCH N), 45.4
2
3
2
2
(CHPh), 49.2 (NCH Ph), 52.2 (COOCH CH ), 62.7
2
2
3
(COOCH ), 65.5 (CHCOOCH ), 77.2 (CH NO ), 121.6 (Im-
3
3
2
2
C5), 126.6 (Im-C4), 128.4 (Ar), 128.6 (Ar), 128.8 (Ar), 129.2
(Ar), 133.6 (Ar), 134.4 (Ar), 135.1 (Ar), 137.5 (Ar), 137.6
(Im-C2), 156.8 (NCOOCH CH ), 170.2 (COOCH ); MS (EI):
-1
g, 96%) as a white solid, m.p. 158-160 °C; IR ν cm : 3400, 1740,
2
3
3
+
1
m/z 492 (M , 1), 445 (13), 355 (18), 310 (25), 91 (100).
1700; H-NMR (DMSO-d ): δ 1.14 (t, 3H, COOCH CH , J = 7.1
6
2
3
Hz.), 1.37 (s, 3H, CCH ), 2.72 (d, 1H, 1/2 ImCH C, J = 16.0 Hz.),
3
2
Methyl (6R*,1'R*)-3-Benzyl-5-ethyloxycarbonyl-6-[2'-nitro-1'-
(1''-trityl-1''H-imida-zol-4''-yl)-ethyl]-4,5,6,7-tetrahydro-3H-imi-
dazo[4,5-c]pyridin-6-carboxylate (6b).
3.19 (d, 1H, 1/2 ImCH C, J = 16.0 Hz.), 3.67 (s, 3H, COOCH ),
2
3
3.97-4.08 (m, 2H, COOCH CH ), 4.26 (d, 1H, 1/2 ImCH N, J =
2
3
2
16.5 Hz.), 4.85 (d, 1H, 1/2 ImCH N, J = 16.5 Hz.), 8.60 (s, 1H,
2
13
Im-H2); C-NMR (DMSO-d ): δ 14.2 (COOCH CH ), 21.5
To a 1 M solution of sodium hexamethyldisilazide in THF (6.5
6
2
3
(CCH ), 28.4 (ImCH CH), 39.3 (ImCH N), 52.2 (COOCH CH ),
ml, 6.45 mmol) stirred at –78 °C under argon atmosphere was
3
2
2
2
3

Sep-Oct 2003
Synthesis of New 4,5,6,7-Tetrahydro-3H-imidazo[4,5-c]pyridine Derivatives
921
added a solution of ester 2 (1.70 g, 4.96 mmol) in dry THF (30 ml).
The mixture was stirred at –78 °C for 1 h. The 4-(2'-nitrovinyl)-1-
trityl-1H-imidazole 5b (2.46 g, 6.45 mmol) dissolved in dry THF
(60 ml) was added at –78 °C and the mixture was then stirred for
12 h at room temperature. The reaction mixture was quenched with
saturated solution of ammonium chloride and extracted with
EtOAc. The combined organic phases were dried over Na SO , fil-
reaction mixture was stirred for 48 h. The catalyst was removed
by filtration through a celite pad and washed with methanol. The
filtrate was evaporated under reduced pressure. The residue was
purified by recrystallization from Et O to give the ester 7b (0.33
2
-1
g, 61%) as a white solid, m.p. 205-206 °C; IR ν cm 3400, 1740,
1700, 1550; H-NMR (DMSO-d ): δ 1.13 (t, 3H, COOCH CH ,
1
6
2
3
J = 7.3 Hz.), 2.90 (d, 1H, 1/2 ImCH C, J = 16.5 Hz.), 3.00 (d, 1H,
2
2
4
1/2 ImCH C, J = 16.5 Hz.), 3.60 (s, 3H, COOCH ), 3.89 (t, 1H,
tered and evaporated to dryness. The residual semisolid was puri-
2
3
CHIm', J = 6.1 Hz.), 3.98-4.06 (m, 2H, COOCH CH ), 4.27 (d,
fied by column chromatography on silica using CHCl /MeOH
2
3
3
1H, 1/2 ImCH N, J = 17.1 Hz.), 4.97 (d, 1H, 1/2 ImCH N, J =
(250:1) as eluent to give a homogeneous residue which was crys-
2
2
17.1 Hz.), 5.19 (d, 2H, CH NO , J = 6.1 Hz.), 6.85 (s, 1H, Im'-
H5), 7.56 (s, 1H, Im'-H2), 7.72 (s, 1H, Im-H2); C-NMR
tallized from cyclohexane to yield the ester 6b (3.35 g, 93%) as a
2
2
13
-1
pale yellow solid, m.p. 122-123°C; IR ν cm : 1730, 1700, 1540;
1
(DMSO-d ): δ 13.6 (COOCH CH ), 24.7 (ImCH CH), 41.0
H-NMR (CDCl ): δ 1.09 (t, 3H, COOCH CH , J = 6.6 Hz.), 2.97
6
2
3
2
3
2
3
(CHIm'), 51.4 (ImCH N), 60.1 (COOCH CH ), 61.6
(d, 1H, 1/2 ImCH C, J = 16.5 Hz.), 3.28 (d, 1H, 1/2 ImCH C, J =
2
2
3
2
2
(COOCH ), 64.1 (CHCOOCH ), 76.6 (CH NO ), 124.7 (Im-
17.0 Hz.), 3.62 (s, 3H, COOCH ), 3.89-4.10 (m, 4H, 1/2 ImCH N
3
3
2
2
3
2
C5), 124.9 (Im'-C5), 133.3 (Im-C4 and Im'-C4), 134.3 (Im-C2),
and COOCH CH and CHIm'), 4.85-5.10 (m, 4H, NCH Ph and
2
3
2
134.9 (Im'-C2), 156.3 (NCOOCH CH ), 168.7 (COOCH ); MS
(ESI): m/z 393 [M+H] .
1/2 CH NO and ImCH N), 5.26 (dd, 1H, 1/2 CH NO , J = 11.9
Hz., J = 10.5 Hz.), 6.57 (s, 1H, Im'-H5), 7.05-7.13 (m, 8H, Ar),
2
3
3
2
2
2
2
2
+
7.31-7.34 (m, 12H, Ar), 7.36 (s, 1H, Im'-H2), 7.44 (s, 1H, Im-H2);
Methyl (6R*,1'R*)-5-Ethyloxycarbonyl-6-[2'-amino-1'-(1''H-
imidazol-4''-yl)-ethyl]-4,5,6,7-tetrahydro-3H-imidazo[4,5-
c]piridin-6-carboxylate (8a).
13
C-NMR (CDCl ): δ 14.0 (COOCH CH ), 27.9 (ImCH CH),
3
2
3
2
39.2 (ImCH N), 40.1 (CHIm'), 49.2 (NCH Ph), 52.2
2
2
(COOCH CH ), 62.5 (COOCH ), 65.2 (CHCOOCH ), 75.3
2
3
3
3
A solution of the ester 7a (0.44 g, 1.09 mmol) in MeOH (35
ml) was hydrogenated over 500 mg of Raney-Ni at 40 psi on a
shaker at room temperature for 6 h. The catalyst was removed by
filtration through a celite pad and washed with methanol. The fil-
trate was evaporated under reduced pressure. The residual semi-
solid was purified by column chromatography on silica using
EtOAc/MeOH (3:1) as eluent to give a homogeneous residue
which was crystallized from EtOAc to yield the ester 8a (0.32 g,
(NCPh ), 77.2 (CH NO ), 121.3 (Im-C5), 121.5 (Im'-C5), 126.8
(Im-C4 and Im'-C4)), 128.0 (Ar), 129.1 (Ar), 129.6 (Ar), 134.5
(Ar), 134.7 (Ar), 135.1 (Ar), 137.4 (Ar), 138.9 (Im-C2), 142.0
3
2
2
(Im'-C2), 156.8 (NCOOCH CH ), 169.9 (COOCH ); MS (ESI):
2
3
3
+
m/z 725 [M+H] .
Methyl (6R*,1'S*)-5-Ethyloxycarbonyl-6-(1'-phenyl-2'-nitro-
ethyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-6-car-
boxylate (7a).
-1
79%) as a white solid, m.p. 203-204 °C; IR ν cm : 3400, 3100,
1
1740, 1710; H-NMR (CD OD): δ 1.24 (t, 3H, COOCH CH , J
To a stirred suspension of the ester 6a (0.83 g, 1.68 mmol) and
10% Pd-C (300 mg) in absolute EtOH (20 ml), cyclohexene (20.4
ml, 201.60 mmol) was added at reflux temperature. The resulting
reaction mixture was stirred for 24 h. The catalyst was removed
by filtration through a celite pad and washed with methanol. The
filtrate was evaporated under reduced pressure. The residual
semisolid was purified by column chromatography on silica
3
2
3
= 6.7 Hz.), 2.62 (d, 1H, 1/2 ImCH C, J = 16.5 Hz.), 3.14 (d, 1H,
2
1/2 ImCH C, J = 16.5 Hz.), 3.54-3.70 (m, 3H, CHPh and
2
CH NH ), 3.75 (s, 3H, COOCH ), 4.08-4.18 (m, 3H,
2
2
3
COOCH CH and 1/2 ImCH N), 5.07 (d, 1H, 1/2 ImCH N, J =
2
3
2
2
16.5 Hz.), 6.93 (br s, 2H, Ar), 7.37 (br s, 3H, Ar), 7.67 (s, 1H, Im-
13
H2); C-NMR (DMSO-d ): δ 14.1 (COOCH CH ), 25.5
6
2
3
(ImCH CH), 40.8 (CH NH ), 47.6 (ImCH N), 51.7 (CHPh),
using CHCl /MeOH (20:1) as eluent to give a homogeneous
2
2
2
2
3
61.1 (COOCH CH ), 61.9 (COOCH ), 65.2 (CHCOOCH ),
residue which was crystallized from EtOAc to yield the ester 7a
2
3
3
3
-1
121.3 (Im-C5), 126.5 (Im-C4), 127.6 (Ar), 127.8 (Ar), 127.9
(Ar), 128.4 (Ar), 129.5 (Ar), 134.7 (Ar), 136.0 (Im-C2), 157.1
(0.54 g, 80%) as a white solid, m.p. 151-152 °C; IR ν cm : 3350,
1
1730, 1700, 1550; H-NMR (CDCl ): δ 1.24 (t, 3H,
3
+
(NCOOCH CH ), 169.7 (COOCH ); MS (EI): m/z 372 (M , 1),
COOCH CH , J = 7.1 Hz.), 2.59 (d, 1H, 1/2 ImCH C, J = 16.5
2
3
3
2
3
2
356 (18), 342 (92), 252 (100), 180 (69), 120 (85), 94 (97).
Hz.), 3.24 (d, 1H, 1/2 ImCH C, J = 16.5 Hz.), 3.78 (s, 3H,
2
COOCH ), 4.04-4.16 (m, 3H, CHPh and COOCH CH ), 4.41 (d,
3
2
3
Methyl (6R*,1'R*)-5-Ethyloxycarbonyl-6-[2'-amino-1'-(1''H-
imidazol-4''-yl)-ethyl]-4,5,6,7-tetrahydro-3H-imidazo[4,5-
c]pyridin-6-carboxylate (8b).
1H, 1/2 ImCH N, J = 17.0 Hz.), 5.16-5.27 (m, 3H, 1/2 ImCH N
2
2
and CH NO ), 6.87-6.70 (m, 2H, Ar), 7.25-7.28 (m, 3H, Ar),
2
2
13
7.63 (s, 1H, Im-H2); C-NMR (CDCl ): δ 14.2 (COOCH CH ),
3
2
3
25.7 (ImCH CH), 42.0 (ImCH N), 45.6 (CHPh), 52.4
A solution of the ester 7b (1.00 g, 2.55 mmol) in MeOH (50 ml)
was hydrogenated over 900 mg of Raney-Ni at 40 psi on a shaker at
room temperature for 3 h. The catalyst was removed by filtration
through a celite pad and washed with methanol. The filtrate was
evaporated under reduced pressure. The residue was purified by
2
2
(COOCH CH ), 62.9 (COOCH ), 65.3 (CHCOOCH ), 77.5
2
3
3
3
(CH NO ), 121.3 (Im-C5), 126.5 (Im-C4), 128.8 (Ar), 128.9
2
2
(Ar), 129.0 (Ar), 129.7 (Ar), 133.9 (Ar), 134.8 (Im-C2), 157.5
+
(NCOOCH CH ), 169.9 (COOCH ); MS (EI): m/z 402 (M , 3),
2
3
3
355 (7), 343 (4), 252 (100), 220 (42), 180 (99), 120 (84), 94 (87).
recrystallization from EtOH/Et O to give the ester 8b (0.82 g, 89%)
2
-1
1
as a white solid, m.p. 201-202 °C; IR ν cm : 3400, 1740, 1700; H-
NMR (CD OD): δ 1.23 (t, 3H, COOCH CH , J = 6.7 Hz.), 2.87 (d,
Methyl (6R*,1'R*)-5-Ethyloxycarbonyl-6-[1'-(1''H-imidazol-4''-
yl)-2'-nitro-ethyl]-4,5, 6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-
6-carboxylate (7b).
3
2
3
1H, 1/2 ImCH C, J = 15.8 Hz.), 3.18 (d, 1H, 1/2 ImCH C, J = 15.8
2
2
Hz.), 3.58 (d, 2H, CH NH , J = 11.0 Hz.), 3.72 (s, 3H, COOCH ),
2
2
3
3.77 (t, 1H, CHIm', J = 11.0 Hz.), 4.11 (q, 2H, COOCH CH , J =
To a stirred suspension of the ester 6b (1.00 g, 1.38 mmol) and
10% Pd-C (600 mg) in absolute EtOH (50 ml), cyclohexene (27.9
ml, 276.00 mmol) was added at reflux temperature. The resulting
2
3
6.7 Hz.), 4.27 (d, 1H, 1/2 ImCH N, J = 16.5 Hz.), 5.09 (d, 1H, 1/2
2
ImCH N, J = 16.5 Hz.), 6.91 (s, 1H, Im'-H5), 7.67 (s, 1H, Im'-H2),
2

922
M. F. Braña, C. Guisado and F. Sanz
Vol. 40
13
3.99 (d, 1H, 1/2 ImCH N, J = 15.9 Hz), 4.42 (d, 1H, CHPh, J =
7.91 (s, 1H, Im-H2); C-NMR (CD OD): δ 14.6 (COOCH CH ),
2
3
2
3
11.0 Hz.), 4.64 (d, 1H, 1/2 ImCH N, J = 15.9 Hz.), 4.98 (d, 1H,
26.9 (ImCH CH), 40.6 (CH NH ), 41.4 (CHIm'), 42.8 (ImCH N),
2
2
2
2
2
1/2 NCH Ph, J = 15.9 Hz.), 5.06 (d, 1H, 1/2 NCH Ph, J = 15.9
52.9 (COOCH CH ), 63.9 (COOCH ), 66.7 (CHCOOCH ), 125.6
2
2
2
3
3
3
Hz.), 5.91 (d, 1H, CHNO , J = 11.0 Hz.), 7.03-7.05 (m, 2H, Ar),
(Im-C5), 129.1 (Im'-C5), 134.4 (Im-C4 and Im'-C4), 136.2 (Im-
C2), 137.5 (Im'-C2), 159.0 (NCOOCH CH ), 171.1 (COOCH );
MS (ESI): m/z 363 [M+H] .
2
7.22-7.24 (m, 3H, Ar), 7.34-7.41 (m, 5H, Ar), 7.50 (s, 1H, Im-
2
3
3
+
13
H2); C-NMR (CDCl ): δ 33.0 (ImCH CH), 37.7 (ImCH N),
3
2
2
49.2 (NCH Ph), 52.9 (CHPh), 54.2 (COOCH ), 69.8
2
3
(6R*,1'S*)-6-(2'-Amino-1'-phenyl-ethyl)-4,5,6,7-tetrahydro-3H-
imidazo[4,5-c]pyridin-6-carboxylic Acid (IIa).
(CHCOOCH ), 87.5 (CHNO ), 119.8 (Im-C5), 126.7 (Im-C4),
3
2
127.5 (Ar), 128.5 (Ar), 128.9 (Ar), 129.2 (Ar), 129.3 (Ar),
A solution of 8a (0.94 g, 2.53 mmol) in HCl 6 N (40 ml,
240.00 mmol) was stirred at reflux temperature for 96 h. After
removal of the solvent under reduced pressure, the residue was
129.4 (Ar), 130.8 (Ar), 133.1 (Ar), 134.6 (Ar), 138.3 (Im-C2),
+
164.4 (NCOCH), 169.7 (COOCH ); MS (EI): m/z 446 (M , 1),
3
414 (14), 400 (21), 355 (51), 91 (100).
purified by recrystallization from EtOH/Et O to give IIa (0.82 g,
2
Crystal Data of Compound 9a.
-1
90%) as a white solid, m.p. 249-250 °C; IR ν cm : 3500, 3440,
1
3150-2450, 1710, 1640; H-NMR (D O): δ 2.90-2.99 (m, 1H, 1/2
C
H
N O , M = 678.73, monoclinic, space group P2 /n. a
40 34 6 5
1
2
ImCH C), 3.12-3.27 (m, 1H, 1/2 ImCH C), 3.37-3.53 (m, 1H,
= 13.131(3) Å, b = 12.130(2) Å, c = 22.230(4) Å, α = δ = 90°, β
2
2
3 3
= 102.26(3)°. V = 3460.1(12) Å , Z = 4, D = 1.303 Mg/m , m =
c
1/2 CH NH ), 3.59-3.71 (m, 1H, 1/2 CH NH ), 3.81-3.84 (m,
2
2
2
2
1H, CHPh), 4.11-4.43 (m, 2H, ImCH N), 7.03-7.15 (m, 2H, Ar),
(Cu-K ) = 0.088, F(000) = 1424. Data collection (4440 collected
2
α
13
7.32 (br s, 3H, Ar), 8.16 (s, 1H, Im-H2); C-NMR (D O): δ 23.1
reflections and 2767 observed reflections [I > 2 σ (Ι)]) were mea-
sured on a Seifert 3003 SC rotating anode diffractometer with
(Cu-Kα) radiation (graphite monochromator) using 2θ−ω scans
at 293(2) K. The structure was solved by direct methods and the
2
(ImCH CH), 27.0 (CH NH ), 37.5 (ImCH N), 45.2 (CHPh),
2
2
2
2
63.3 (CHCOOH), 121.0 (Im-C5), 123.1 (Im-C4), 124.4 (Ar),
127.9 (Ar), 128.3 (Ar), 128.4 (Ar), 128.6 (Ar), 134.0 (Ar), 136.4
+
(Im-C2), 171.0 (COOH). MS (ESI): m/z 287 [M+H] .
non-hydrogen atoms were refined anisotropically by full-matrix
2
Anal. Calcd. for C H N O •2HCl•0.75H O: C, 48.33; H,
least squares based on F to give the agreement factors R =
1
15 18
4
2
2
5.81; N, 15.03. Found: C, 48.58; H, 5.63; N, 14.73.
0.0370, wR = 0.0743.
2
(6R*,1'R*)-6-[2'-Amino-1'-(1''H-imidazol-4''-yl)-ethyl]-4,5,6,7-
tetrahydro-3H-imidazo[4,5-c]pyridin-6-carboxylic Acid (IIb).
Methyl (7S*,8R*,8aR*)-3-Benzyl-8-(1'-trityl-1'H-imidazol-4'-
yl)-7-nitro-6-oxo-3,4,6,7, 8,9-hexahydroimidazo[4,5-f]indolizin-
8a-carboxilate (9b).
A solution of 8b (0.61 g, 1.68 mmol) in HCl 6 N (30 ml, 180.00
mmol) was stirred at reflux temperature for 168 h. After removal
of the solvent under reduced pressure, the residue was purified by
To a solution of the ester 6b (0.27 g, 0.37 mmol) in MeOH (20
ml) was added a solution 1 N NaOH (0.4 ml). The reaction mix-
ture was heated at reflux for 24 h. The residue was taken up in
water and neutralized with 3 N HCl. MeOH was evaporated
under reduced pressure and the aqueous layer was extracted with
EtOAc. The organic layer was washed with saturated aqueous
sodium chloride, dried over Na SO , filtered and concentrated
recrystallization from EtOH/Et O to give IIb (0.65 g, 92%) as a
2
-1
white solid, m.p. 206-207 °C; IR ν cm 3400, 3120, 1720, 1620;
H-NMR (D O): δ 2.78 (d, 1H, 1/2 ImCH C, J = 17.0 Hz.), 2.87
1
2
2
(d, 1H, 1/2 ImCH C, J = 17.0 Hz.), 3.47 (dd, 1H, 1/2 CH NH , J
2
2
2
= 11.0 Hz., J = 7.7 Hz.), 3.76 (t, 1H, 1/2 CH NH , J = 9.6 Hz.),
2
2
2
4
3.95 (t, 1H, CHIm', J = 7.7 Hz.), 4.11 (d, 1H, 1/2 ImCH N, J =
under reduced pressure. The residual semisolid was purified by
2
16.5 Hz.), 4.28 (d, 1H, 1/2 ImCH N, J = 16.5 Hz.), 7.42 (s, 1H,
Im'-H5), 8.41 (s, 1H, Im'-H2), 8.50 (s, 1H, Im-H2); C-NMR
column chromatography on silica using CHCl /MeOH (20:1) as
eluent to give a homogeneous residue which was crystallized
2
3
13
(D O): δ 26.0 (ImCH CH), 39.5 (CH NH ), 42.4 (CHIm'), 46.4
from EtOAc to yield 9b (0.22 g, 88%) as a pale yellow solid, m.p.
2
2
2
2
-1
1
(ImCH N), 64.2 (CHCOOH), 120.7 (Im-C5 and Im-C5), 131.0
201-202 °C; IR ν cm : 1740, 1730, 1550; H-NMR (CDCl ): δ
2
3
(Im-C4), 131.1 (Im'-C4), 136.5 (Im-C2), 137.0 (Im'-C2), 184.1
(COOH); MS (ESI): m/z 277 [M+H] .
2.88 (d, 1H, 1/2 ImCH C, J = 15.0 Hz.), 3.44 (s, 3H, COOCH ),
2
3
+
3.75 (d, 1H, 1/2 ImCH C, J = 15.0 Hz.), 3.97 (d, 1H, 1/2
2
Anal. Calcd. for C H N O •4HCl•2H O: C, 31.45; H, 5.24;
ImCH N, J = 15.4 Hz.), 4.31 (d, 1H, CHIm', J = 10.4 Hz.), 4.59
12 16 6´
2
2
2
N, 18.34. Found: C, 31.08; H, 5.23; N, 18.01.
(d, 1H, 1/2 ImCH N, J = 15.4 Hz.), 4.97 (d, 1H, 1/2 NCH Ph, J =
2
2
15.9 Hz.), 5.04 (d, 1H, 1/2 NCH Ph, J = 16.5 Hz.), 6.15 (d, 1H,
2
Methyl (7S*,8S*,8aR*)-3-Benzyl-8-phenyl-7-nitro-6-oxo-
3,4,6,7,8,9-hexahydroimidazo[4,5-f]indolizin-8a-carboxylate
(9a).
CHNO , J = 10.4 Hz.), 6.85 (s, 1H, Im'-H5), 7.02-7.10 (m, 7H,
2
13
Ar and Im'-H2), 7.35 (br s, 14H, Ar), 7.51 (s, 1H, Im-H2); C-
NMR (CDCl ): δ 29.6 (ImCH CH), 32.8 (ImCH N), 37.6
3
2
2
To a solution of the ester 6a (0.24 g, 0.49 mmol) in MeOH
(30 ml) was added a solution 1 N NaOH (0.5 ml). The reaction
mixture was heated at reflux for 24 h. The residue was taken up
in water and neutralizated with 3 N HCl. MeOH was evaporated
under reduced pressure and the aqueous layer was extracted
with EtOAc. The organic layer was washed with saturated
(CHIm'), 48.9 (NCH Ph), 53.3 (COOCH ), 68.4 (CHCOOCH ),
2
3
3
75.6 (NCPh ), 87.4 (CH NO ), 119.9 (Im-C5), 120.9 (Im'-C5),
3
2
2
126.7 (Im-C4 and Im'-C4)), 128.2 (Ar), 128.5 (Ar), 129.2 (Ar),
129.6 (Ar), 131.1 (Ar), 133.1 (Ar), 134.6 (Ar), 138.1 (Im-C2),
139.4 (Im'-C2), 165.0 (NCOCH), 169.2 (COOCH ); MS (EI):
3
m/z 435 (1%), 345 (11), 243 (100), 165 (72), 91 (40).
aqueous sodium chloride, dried over Na SO , filtered and con-
centrated under reduced pressure. The residue was purified by
2
4
Crystal Data of Compound 9b.
C
H
N O , M = 446.46, triclinic, space group P-1. a =
recrystallization from EtOAc/hexane to give 9a (0.21 g, 96%)
24 22 4 5
-1
9.068(2) Å, b = 11.615(2) Å, c = 11.774(2) Å, α = 107.36(3)°, β
= 100.35(3)°, δ = 106.63(3)°. V = 1085.4(4) Å , Z = 2, D =
1.366 Mg/m , m = (Cu-K ) = 0.098, F(000) = 468. (3579 col-
as a white solid, m.p. 204-205 °C; IR ν cm : 1730, 1710, 1560;
3
1
H-NMR (CDCl ): δ 3.10 (d, 1H, 1/2 ImCH C, J = 15.3 Hz.),
c
3
2
3
3.25 (s, 3H, COOCH ), 3.82 (d, 1H, 1/2 ImCH C, J = 15.3 Hz.),
α
3
2

Sep-Oct 2003
Synthesis of New 4,5,6,7-Tetrahydro-3H-imidazo[4,5-c]pyridine Derivatives
923
302, 832 (1983).
lected reflections and 1019 observed reflections [I > 2 σ (I)]).
[2] J.-M. Arrang, M. Garbarg and J.-C. Schwartz,
Neuroscience, 23, 149 (1987).
[3] J.-M. Arrang, M. Garbarg and J.-C. Schwartz,
Neuroscience, 15, 553 (1985).
[4] J. L. Burgaur and N. Oudart, J. Pharm. Pharmacol., 45,
955 (1993).
[5] E. Schlicker, B. Malinowska, M. Kathmann and M.
Göthert, Fundam. Clin. Pharmacol., 8, 128, 1994.
[6] X. Ligneau, M. Garbarg, M. L. Vizuete, J. Díaz, K.
Purand, H. Stark, W. Schunack and J.-C. Schwartz, J. Pharmacol.
Exp. Ther., 271, 452 (1994).
[7] H. Stark, E. Schlicker and W. Schunack, Drugs Future, 21,
507 (1996).
[8] I. J. P. de Esch, R. C. Vollinga, K. Goubitz, H. Schenck, U.
Appelberg, U. Hacksell, S. Lemstra, O. P. Zuiderveld, M. Hoffmann,
R. Leurs, W. M. P. B. Menge and H. Timmerman, J. Med. Chem., 42,
1115 (1999).
[9] R. C. Vollinga, J. P. Koning, F. P. Jansen, R. Leurs, W. M.
P. B. Menge and H. Timmerman, J. Med. Chem., 37, 332 (1994).
[10] A. C. Chibnall, J. Biol. Chem., 61, 303 (1924).
[11] S. Klutchko, J. C. Hodges, C. J. Blankley and N. L.
Colbry, J. Heterocyclic Chem., 28, 97 (1991).
[12] G. M. Anantharamaiah and K. M. Sivanandaiah, J. Chem.
Soc., Perkin Trans. I, 490 (1977).
Final values were R = 0.1099, wR = 0.2444.
1
2
4-(2'-Nitrovinyl)-1-trityl-1H-imidazol (5b).
A mixture of 1-trityl-1H-imidazol-4-carboxaldehyde [15]
(12.01 g, 35.48 mmol), nitromethane (35.5 ml, 656.82 mmol),
glacial acetic acid (10.6 ml) and ammonium acetate (5.41 g) was
sonicated at 22 °C for 6 h. After removal of the solvent, the
residue was dissolved into CH Cl and washed with saturated
2
2
aqueous sodium chloride. The organic layer was dried over
Na SO , filtered and evaporated until dryness. The residue was
2
4
purified by recrystallization from THF to give 5b (7.07 g, 52%)
-1
as a pale yellow solid, m.p. 228-229 °C; IR ν cm : 1640, 1490;
1
H-NMR (CDCl ): δ 7.10-7.14 (m, 6H, Ar), 7.26 (s, 1H, Im-H5),
3
7.38 (sa, 9H, Ar), 7.52 (s, 1H, Im-H2), 7.75 (d, 1H, J 12.1,
13
CH=CHNO ), 7.83 (s, 1H, CH=CHNO , J = 12.1 Hz.); C-
2
2
NMR (CDCl ) δ 75.4 (NCPh ), 126.6 (Im-C5), 127.5 (Im-C4),
3
3
127.7 (Ar), 128.2 (Ar), 128.5 (Ar), 129.1 (Ar), 132.5 (Ar), 132.6
(Ar), 134.5 (Im-C2), 141.1 (CH=CHNO ), 141.6 (CH=CHNO ).
2
2
Acknowledgments.
The authors wish to thank Professor L.F. Alguacil's group for
the biological evaluation of these compounds. C.Guisado also
thanks the Ministerio de Educación y Ciencia (AP96 33987907)
and the Universidad San Pablo CEU for the fellowship.
Continuos support from Universidad San Pablo CEU is greatfully
acknowledged.
[13] J. McNulty, J. A. Steere and S. Wolf, Tetrahedron Lett.,
39, 8013 (1998).
[14] J. M. Arrang, M. Garbarg and J. C. Schwartz, Eur. J.
Pharmacol., 188, 219 (1990).
REFERENCES AND NOTES
[15] J. L. Kelley, C. A. Miller and E. W. J. McLean, J. Med.
Chem., 20, 721 (1977).
[1] J.-M. Arrang, M. Garbarg and J.-C. Schwartz, Nature,