Synthesis of 1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-ones as conformationally constrained pyrazole analogues of histamine

Article abstract of DOI:10.1055/s-0030-1257864

Three synthetic methods for the preparation of 1,5-disubstituted 1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-ones as heterocyclic histamine analogues were developed. The first method starts from easily available methyl 5-(2-aminoethyl)-1H-pyrazole-4-carboxylates, which were N-alkylated and the resulting secondary amines were cyclised in the presence of a base to give the title compounds in 17-92% yields (method A). Alternatively, the amines were first cyclised to the 5-unsubstituted pyrazolo[4,3-c]pyridin-4-ones. Subsequent N-benzylation afforded three of the title compounds in 36-49% yields (method B). The third method comprises a six-step transformation of methyl acrylate into 1-benzylpiperidine-2,4-dione. Treatment of the latter with N,N-dimethylformamide dimethylacetal (DMFDMA) followed by acid-catalysed cyclisation of the formed enaminone with methyl-, phenyl- and tert-butylhydrazine afforded the same three title compounds in 79-87% yields (method C). Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1257864

PAPER
3363
Synthesis of 1,5,6,7-Tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-ones as
Conformationally Constrained Pyrazole Analogues of Histamine
Pyrazole
A
nalogue
a
s
of
H
istam
r
ine ja Žerovnik,a Uroš Grošelj,a David Kralj,a Črt Malavašič,a Jure Bezenšek,a Georg Dahmann,b Katarina Stare,a
Anton Meden,a Branko Stanovnik,a Jurij Svete*a
a
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, P.O. Box 537, 1000 Ljubljana, Slovenia
Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Chemical Research, 88397 Biberach, Germany
b
Fax +386(1)2419220; E-mail: jurij.svete@fkkt.uni-lj.si
Received 21 April 2010; revised 9 June 2010
HO
R
Abstract: Three synthetic methods for the preparation of 1,5-disub-
stituted 1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-ones as
heterocyclic histamine analogues were developed. The first method
starts from easily available methyl 5-(2-aminoethyl)-1H-pyrazole-
4-carboxylates, which were N-alkylated and the resulting secondary
amines were cyclised in the presence of a base to give the title com-
pounds in 17–92% yields (method A). Alternatively, the amines
were first cyclised to the 5-unsubstituted pyrazolo[4,3-c]pyridin-4-
ones. Subsequent N-benzylation afforded three of the title com-
pounds in 36–49% yields (method B). The third method comprises
a six-step transformation of methyl acrylate into 1-benzylpiperi-
dine-2,4-dione. Treatment of the latter with N,N-dimethylforma-
mide dimethylacetal (DMFDMA) followed by acid-catalysed
cyclisation of the formed enaminone with methyl-, phenyl- and tert-
butylhydrazine afforded the same three title compounds in 79–87%
yields (method C).
H
N
R
NH2
NH2
tyramine (R = H)
dopamine (R = OH)
tryptamine (R = H)
serotonine (R = OH)
H
N
H
N
N
MeO
NH2
NHAc
melatonin
histamine
Figure 1
Key words: enaminones, cyclisation, alkylation, pyrazolo[4,3-
c]pyridine, histamine
In the last decade, a substantial part of our research has
been focused on the synthesis of functionalised pyrazoles
through (a) 1,3-dipolar cycloaddition of (4R*,5R*)-4-ben-
zoylamino-5-phenyl-3-pyrazolidinone-derived azometh-
ine imines to various dipolarophiles,6 and (b) cyclo-
condensation of functionalised enaminones with mono-
substituted hydrazines.7 In particular, b-(dimethylamino)-
enones, which are stable b-keto aldehyde analogues, have
found use as versatile reagents in heterocyclic synthesis
including combinatorial applications.8 Within this con-
text, we recently reported a simple four-step synthesis of
1-substituted 4-(2-aminoethyl)-1H-pyrazol-5-ols as pyra-
zole analogues of histamine.9 Soon after, a one-pot, paral-
lel, solution-phase synthesis of these compounds was also
developed.10 In a continuation, we reported the synthesis
of 5-(2-aminoethyl)-1H-pyrazol-4-carboxamides as relat-
ed pyrazole analogues of histamine analogues.11 In an ex-
tension of this study, we found some intriguing further
transformations of the above histamine analogues. Name-
ly, N-alkylation of the 5-aminoethyl group followed by
cyclisation to the 4-carboxyl group should provide access
to 4H-pyrazolo[4,3-c]pyridin-4-ones as bicyclic ana-
logues of histamine. Herein, we report the results of our
study on the synthesis of 1,5-disubstituted 1,5,6,7-tetrahy-
dro-4H-pyrazolo[4,3-c]pyridin-4-ones 4, as novel and
conformationally constrained histamine analogues.
Functionalised heterocycles represent important scaffolds
for the preparation of compound libraries for medicinal
and pharmaceutical applications, due to their ability to
mimic structures of peptides and to reversibly bind to pro-
teins.1,2 Because of the crucial role of histamine, tyramine,
dopamine, tryptamine, serotonin and melatonin (Figure 1)
as chemical messengers in biological processes, the prep-
aration of novel synthetic analogues based on the 2-(het-
eroaryl)ethylamine scaffold represents an important target
in medicinal and synthetic organic chemistry.3,4
Despite their rare occurrence in nature, pyrazole and its
derivatives are certainly an important class of heterocyclic
compounds. Numerous pyrazole derivatives have found
use in various applications, and a general interest in the
chemistry of pyrazoles is still continuing. Among the var-
ious synthetic options available for the construction of the
pyrazole ring, two classical approaches are most frequent-
ly employed. The first is based on a cyclocondensation re-
action between a 1,3-dicarbonyl compound (or its
analogue) and a hydrazine derivative, whilst the second is
based on the cycloaddition of a C–N–N type 1,3-dipole
(diazoalkane, nitrile imine or azomethine imine) to a C=C
multiple bond.5
First, we undertook the synthesis of the title compounds 4
via d-amino esters 2 as the key intermediates. Compounds
2a and 2b were prepared in four steps from commercially
available Boc-b-alanine (1) following a literature proce-
SYNTHESIS 2010, No. 19, pp 3363–3373
Advanced online publication: 22.07.2010
DOI: 10.1055/s-0030-1257864; Art ID: T09210SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
0

3364
D. Žerovnik et al.
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dure.11 In the same manner, the novel compound 2c was amide then furnished compounds 4a, 4e and 4i in
also obtained in 86% yield by acidolytic deprotection of moderate yields (Scheme 1, Method B, Table 1).
its known Boc-derivative.11 Two methods were studied
COOMe
COOR'
COOMe
for the preparation of title compounds: alkylation of the
primary amino group followed by base-catalysed lactami-
sation (method A), and base-catalysed lactamisation fol-
lowed by alkylation of the amido group (method B).
Alkylations of amines 2a–c were carried out in two ways:
(a) with either benzaldehyde or pyridine-2-carbaldehyde
in the presence of sodium borohydride and acetic acid
(procedure A),12 or (b) by catalytic hydrogenation in the
presence of 10% Pd/C and tetrahydrofuran-3-carbalde-
hyde or acetone (procedure B). In this manner, the
monoalkylated amines 3a–i, 3k and 3l were obtained in
22–80% yield. Reductive alkylation of 2c with pyridine-
2-carbaldehyde was exceptional, since it directly afforded
the cyclisation product 4j in 22% yield. Somewhat sur-
prisingly, compounds 3a–i,k,l were more reluctant to cy-
clise, and required harsher reaction conditions. Treatment
of these compounds with excess potassium tert-butoxide
in 1-propanol heated at reflux for 15 hours furnished the
title compounds 4a–i,k,l in 11–92% yield (Scheme 1,
method A, Table 1).
iv, v
i–iii
one pot
O
R
N
6
Ph
R
N
7 (R = H, R' = Me)
8 (R = Boc, R' = Me)
9 (R = Boc, R' = H)
Ph
10 (R = Boc)
11 (R = H⋅HCl)
Ph
Ph
N
O
N
O
vii
viii
vi
H
O
O
NMe2
13
R1
12
N
N
4a: R1 = Me
4e: R1 = Ph
4i: R1 = t-Bu
N
Ph
O
4a,e,i
Boc-β-AlaOH (1)
2a, 5a: R1 = Me
2b, 5b: R1 = Ph
Scheme 2 Synthesis of 4 by method C. Reagents and conditions: (i)
benzylamine, DBU (0.05 equiv), r.t.; (ii) Boc2O, MeCN, r.t.; (iii) aq 2
M NaOH, MeOH, r.t., then acidification with aq 6 M HCl (0.9 equiv)
and aq 1 M NaHSO4 (0.2 equiv) r.t.; (iv) CDI, THF, r.t., then
MeO2CCH2CO2K, MgCl2, THF, r.t.; (v) 2 M HCl–EtOAc, 0–20 °C;
(vi) aq 1 M NaOH, r.t., then aq 1 M HCl, r.t.; (vii) DMFDMA, tolu-
ene, r.t.; (viii) R3NHNH2·HCl, 2-methoxyethanol, r.t.→reflux.
4 steps
ref. 11
2c, 5c: R1 = t-Bu
R1
R1
N1
HCl
1'
5
N
N 2
N
iv
H2N
2'
method B
3
4
HN
MeOOC
In the third synthetic approach, 1-benzylpiperidine-2,4-
dione (12)13 was used as the key intermediate, which was
transformed into the title compounds 4 (method C). Sol-
vent-free 1,8-diazabicyclo[5.4.0]undec-7-ene-catalysed
Michael addition of benzylamine to methyl acrylate (6)
gave the N-benzyl-b-alanine ester (7),14 which was treated
with Boc2O. The so-formed methyl N-benzyl-b-alaninate
(8)15 was hydrolysed with aqueous sodium hydroxide to
give 916 in 79% yield over three steps. Thus, our synthetic
procedure for the preparation of 9 was simpler and more
efficient than previously described methods,16a,c which
gave 9 in significantly lower overall yields. Subsequent
Masamune–Claisen condensation17 of the crude product 9
with magnesium monomethyl malonate was performed
according to the procedure described previously for ho-
mologation of closely related Boc-b-alanine11 and gave b-
keto ester 10 in 92% yield. Acidolytic removal of the Boc
group afforded methyl 5-(benzylamino)-3-oxopentanoate
hydrochloride (11), which was then cyclised under basic
conditions to give 1-benzylpiperidine-2,4-dione (12) in
66% yield over three steps (from 9). From this point on,
formation of the condensed pyrazole ring was achieved by
using the standard enaminone protocol, i.e., by reaction of
the active methylene compound 12 with N,N-dimethyl-
formamide dimethylacetal (DMFDMA) followed by cy-
clocondensation of the so-formed enamino ketone 13 with
hydrazines. Thus, treatment of 12 with DMFDMA in an-
O
2a–c
5a–c
i or ii
method A
v
R1
R1
7a N1
7
N
H
N 2
iii
N
N
6
R2
3
5 N
3a
MeOOC
R2
4
O
3a–l
4a–l
Scheme 1 Synthesis of 4 by methods A and B. Reagents and condi-
tions: (i) benzaldehyde or pyridine-2-carbaldehyde, NaBH4, MeOH,
AcOH, 0 °C→r.t. (procedure A12); (ii) tetrahydrofuran-3-carbalde-
hyde or acetone, H2 (3 bar), 10% Pd–C, r.t. (procedure B); (iii) t-
BuOK, 1-propanol, reflux; (iv) Et3N, DMF, reflux; (v) t-BuOK,
DMF, r.t., then BnBr, r.t.
In another synthetic approach to the title compounds 4, the
d-amino esters 2 were first cyclised to the 5-unsubstituted
pyrazolo[4,3-c]pyridin-4-ones 5, followed by N-alkyla-
tion. The d-amino esters 2a–c were cyclised thermally in
a mixture of N,N-dimethylformamide and triethylamine,
to afford pyrazolo[4,3-c]pyridin-4-ones 5a–c in 45–66%
yield. Subsequent N-benzylation of 5a–c with benzyl bro-
mide and potassium tert-butoxide in N,N-dimethylform-
Synthesis 2010, No. 19, 3363–3373 © Thieme Stuttgart · New York

PAPER
Pyrazole Analogues of Histamine
3365
hydrous toluene at room temperature gave the enamino- ods were developed. Methods A and B are six-step syn-
derivative 13 in 88% yield. Subsequent cyclisation of 13 theses starting from Boc-b-alanine (1), which is
with methylhydrazine, phenylhydrazine or tert-butylhy- transformed in four steps into the key intermediates 2 ac-
drazine was carried out in 2-methoxyethanol at reflux to cording to the procedure reported previously.11 From this
furnish the desired pyrazolo[4,3-c]pyridin-4-ones 4a,e,i point on, two complementary synthetic pathways are fea-
in 79–87% yield (Scheme 2, Table 1).
sible: (a) reductive N-alkylation of the amine 2 followed
by cyclisation to 4 (method A), and (b) cyclisation of 2
into the 4H-pyrazolo[4,3-c]pyridin-4-one 5 followed by
N-alkylation with alkyl halide (method B). Method C
comprises a seven-step transformation of methyl acrylate
(6) into 1-benzyl-3-[(dimethylamino)methylidene]piperi-
dine-2,4-dione (13) and subsequent cyclisation with
monosubstituted hydrazines. At first glance, all three
methods seem somewhat lengthy, however, steps 1→2
(methods A and B) and 6→9 (method C) can be carried
out as one-pot transformations. In summary, methods A–
C represent efficient synthetic approaches to bicyclic his-
tamine analogues 4 with variable substituents at N(1) and
N(5). Each of the N-substituents can be introduced at dif-
ferent stages of the synthesis, while three different types
of common reagents (aldehydes and ketones, alkyl ha-
lides, and primary amines) can be employed for the intro-
duction of the N(5)-substituent.
The structures of novel compounds 2c, 3a–i,k,l, 4a–l, 10,
11 and 13 were determined by spectroscopic (IR, NMR
and MS) methods and by CHN elemental analyses. Com-
pounds 4c,d,k, 10 and 13 were not obtained in analytically
pure form; their identities were confirmed by 13C NMR
and HRMS analyses. Physical and spectral data for known
compounds 2a,b,11 7,14 8,15 916 and 1213 were in agreement
with data reported in the literature. Intermediates 714 and
815 were not isolated in pure form and were characterised
1
only by H NMR analysis. Additional characterisation
data for known compound 916 are also given in Table 1
and Table 2. The structures of compounds 4a and 4i were
also determined by X-ray diffraction analyses.
In conclusion, twelve 1,5-disubstituted 1,5,6,7-tetrahy-
dro-4H-pyrazolo[4,3-c]pyridin-4-ones 4 as novel, confor-
mationally constrained pyrazole analogues of histamine
were synthesised. Three complementary synthetic meth-
Table 1 Experimental Data for Compounds 2–5, 9–11 and 13
Compd
R1
R2
Proc.
Yield (%) Mp (°C)
Molecular formula, analysis data
ESI-MS (m/z),
HRMS
C11H19N3O2·HCl
226 [M + H]+
2c
t-Bu
Me
Me
–
–
86
22
47
173–179
183–188
123–127
Calcd.: C, 50.40; H, 7.70; N, 16.05
Found: C, 50.04; H, 7.89; N; 16.18
Calcd.: 226.1556
Found: 226.1547
C15H19N3O2·1HCl
Calcd.: C, 57.31; H, 6.45; N, 13.37
Found: C, 57.37; H, 6.60; N, 13.41
274 [M + H]+
Calcd.: 274.1556
Found: 274.1552
3a
A
C14H18N4O2·2HCl
Calcd.: C, 47.80; H, 5.77; N, 15.93
Found: C, 47.97; H, 6.56; N, 15.87
275 [M + H]+
Calcd.: 275.1508
Found: 275.1509
N
3b
A
268 [M + H]+
O
C13H21N3O3·1HCl
3c
Me
B
73
141–144
Calcd.: C, 50.64; H, 7.23; N, 13.63
Found: C, 50.69; H, 7.45; N, 13.47
Calcd.: 268.1661
Found:268.1660
C11H19N3O2·HCl
Calcd.: C, 50.48; H, 7.70; N, 16.05
Found: C, 50.10; H, 7.79; N, 15.84
3d
3e
3f
Me
Ph
Ph
B
A
A
33
52
47
220–225
176–180
166–174
226 [M + H]+
336 [M + H]+
337 [M + H]+
C20H21N3O2·HCl
Calcd.: C, 64.60; H, 5.96; N, 11.30
Found: C, 64.65; H, 6.08; N, 11.38
C19H20N4O2·2HCl
Calcd.: C, 55.75; H, 5.42; N, 13.69
Found: C, 55.71; H, 5.69; N, 13.51
N
330 [M + H]+
O
C18H23N3O3·1HCl
3g
Ph
B
63
148–155
Calcd.: C, 58.37; H, 6.56; N, 11.34
Found: C, 58.28; H, 6.84; N, 11.30
Calcd.: 330.1818
Found: 330.1810
Synthesis 2010, No. 19, 3363–3373 © Thieme Stuttgart · New York

3366
D. Žerovnik et al.
PAPER
Table 1 Experimental Data for Compounds 2–5, 9–11 and 13 (continued)
Compd
R1
Ph
R2
Proc.
B
Yield (%) Mp (°C)
Molecular formula, analysis data
ESI-MS (m/z),
HRMS
C16H21N3O2·1 HCl
Calcd.: C, 58.52; H, 6.79; N, 12.80
Found: C, 58.52; H, 7.01; N, 12.74
288 [M + H]+
Calcd.: 288.1712
Found: 288.1713
3h
80
209–213
C18H25N3O2·HCl
Calcd.: C, 61.44; H, 7.45; N, 11.94
Found: C, 61.71; H, 7.49; N, 12.17
316 [M + H]+
3i
t-Bu
t-Bu
A
A
44
–
176–180
–
N
3ja
–
–
O
C16H27N3O3·HCl
Calcd.: C, 55.56; H, 8.16; N, 12.15
Found: C, 55.57; H, 8.28; N, 12.10
3k
t-Bu
B
54
172–177
310 [M + H]+
C14H25N3O2·1 HCl
268 [M + H]+
3l
t-Bu
Me
B
–
43
188–194
97–100
Calcd.: C, 54.53; H, 8.54; N, 13.63
Found: C, 54.71; H, 8.75; N, 13.74
Calcd.: 268.2025
Found: 268.2023
72b
36c
79d
C14H15N3O
Calcd.: C, 69.69; H, 6.27; N, 17.41
Found: C, 69.96; H, 6.20; N, 17.33
242 [M + H]+
Calcd.: 242.1293
Found: 242.1291
4a
4b
C13H14N4O· H2O
Calcd.: C, 62.89; H, 5.95; N, 22.57
Found: C, 62.93; H, 5.42; N, 22.40
243 [M + H]+
Calcd.: 243.1246
Found: 243.1250
N
Me
–
45
54
52
111–114
236 [M + H]+
Calcd.: 236.1399
Found: 236.1400
O
4c
Me
–
oil
C12H17N3O2
C10H15N3O
194 [M + H]+
Calcd.: 194.1293
Found: 194.1285
4d
4e
4f
Me
Ph
Ph
–
–
–
72–75
136–138
95–99
89b
49c
86d
C19H17N3O
Calcd.: C, 75.23; H, 5.65; N, 13.85
Found: C, 75.06; H, 5.76; N, 13.80
304 [M + H]+
305 [M + H]+
C18H16N4O
Calcd.: C, 71.04; H, 5.30; N, 18.41
Found: C, 70.62; H, 5.23; N, 18.32
N
66
77
17
O
C17H19N3O2
Calcd.: C, 68.67; H, 6.44; N, 14.13
Found: C, 68.76; H, 6.46; N, 14.02
4g
Ph
–
79–83
298 [M + H]+
C15H17N3O
Calcd.: C, 70.56; H, 6.71; N, 16.46
Found: C, 70.50; H, 6.81; N, 16.55
4h
4i
Ph
–
–
–
212–217
77–79
256 [M + H]+
284 [M + H]+
92b
38c
87d
C17H21N3O
Calcd.: C, 72.06; H, 7.47; N, 14.83
Found: C, 71.85; H, 7.37; N, 14.85
t-Bu
t-Bu
C16H20N4O·2HCl
Calcd.: C, 51.18; H, 6.04; N, 14.92
Found: C, 51.24; H, 6.49; N, 14.68
285 [M + H]+
Calcd.: 285.1715
Found: 285.1704
N
4j
22
81
136–143
278 [M + H]+
Calcd.: 278.1869
Found: 278.1870
O
4k
t-Bu
–
oil
C15H23N3O2
Synthesis 2010, No. 19, 3363–3373 © Thieme Stuttgart · New York

PAPER
Pyrazole Analogues of Histamine
3367
Table 1 Experimental Data for Compounds 2–5, 9–11 and 13 (continued)
Compd
R1
t-Bu
Me
Ph
t-Bu
–
R2
Proc.
Yield (%) Mp (°C)
Molecular formula, analysis data
ESI-MS (m/z),
HRMS
C13H21N3O
Calcd.: C, 66.35; H, 8.99; N, 17.86
Found: C, 66.75; H, 9.21; N, 17.85
4l
–
–
–
–
–
–
–
–
70
45
66
51
79
70
93
83
135–138
197–200
202–205
164–166
oil
236 [M + H]+
C7H9N3O
Calcd.: C, 55.62; H, 6.00; N, 27.80
Found: C, 55.49; H, 6.27; N, 27.63
152 [M + H]+
Calcd.: 152.0824
Found: 152.0821
5a
–
–
–
–
–
–
–
C12H11N3O
Calcd.: C, 67.59; H, 5.20; N, 19.71
Found: C, 67.65; H, 5.15; N, 19.69
214 [M + H]+
Calcd.: 214.0980
Found: 214.0990
5b
5c
C10H15N3O
Calcd.: C, 62.15; H, 7.82; N, 21.74
Found: C, 62.06; H, 8.11; N, 21.66
194 [M + H]+
Calcd.: 194.1293
Found: 194.1291
278 [M – H]+
Calcd.: 278.1392
Found: 278.1396
9
C15H21NO4
C18H25NO5
358 [M + Na]+
Calcd.: 358.1644
Found: 358. 1630
10
–
oil
C18H18NO3·HCl
Calcd.: C, 57.46; H, 6.68; N, 5.15
Found: C, 57.45; H, 6.77; N, 5.44
236 [M + H]+
Calcd.: 236.1287
Found: 236.1290
11
–
141–148
oil
259 [M + H]+
Calcd.: 259.1447
Found: 259.1443
13
–
C15H18N2O2
a Not isolated.
b Method A (Scheme 1).
c Method B (Scheme 1).
d Method C (Scheme 2).
Table 2 Spectral Data for Compounds 2–5, 9–11 and 13
Compd IR (cm–1)
NMR (d, ppm)a
2c
3449, 2965, 2913, 2828, 2752, 2654, 2616, 2552,
2512, 2454, 2047, 1709, 1605, 1551, 1508, 1465,
1438, 1402, 1368, 1291, 1244, 1213, 1154, 1099,
1004, 942, 872, 809, 783, 753, 614, 555, 497
1H NMR: 1.64 (s, 9 H, t-Bu), 2.93–3.05 (m, 2 H, 1¢-CH2), 3.44–3.52 (m, 2 H,
+
2¢-CH2), 3.77 (s, 3 H, OCH3), 7.79 (s, 1 H, 3-H), 8.38 (br s, 3 H, NH3 )
13C NMR: 24.1, 30.1, 37.7, 51.1, 61.3, 112.9, 138.3, 141.8, 163.1
3a
3518, 3428, 3057, 2938, 2759, 2616, 2415, 1819,
1717, 1553, 1495, 1441, 1358, 1293, 1237, 1177,
1H NMR: 3.03–3.15 (m, 2 H, 1¢-CH2), 3.44 (dd, J = 7.2, 9.0 Hz, 2 H, 2¢-CH2),
3.74 (s, 3 H, 1-CH3), 3.89 (s, 3 H, OCH3), 4.17 (t, J = 5.8 Hz, 2 H, CH2Ph),
1147, 1097, 1027, 980, 931, 894, 806, 780, 746, 700, 7.40–7.49 (m, 3 H, o,p-PhH), 7.57–7.64 (m, 2 H, m-PhH), 7.80 (s, 1 H, 3-H),
+
625, 594, 536, 501, 424
9.85 (br s, 2 H, NH2 )
13C NMR: 21.2, 36.8, 44.4, 49.8, 51.0, 111.2, 128.5, 128.8, 130.0, 132.0,
139.9, 142.0, 163.0
3b
3460, 3243, 2917, 2697, 2557, 2412, 1711, 1667,
1618, 1561, 1472, 1445, 1406, 1372, 1299, 1275,
1H NMR: 3.14–3.24 (m, 2 H, 1¢-CH2), 3.40–3.47 (m, 2 H, 2¢-CH2), 3.75 (s,
3 H, 1-CH3), 3.88 (s, 3 H, OCH3), 4.36 (br s, 2 H, CH2Py), 7.49 (ddd, J = 1.0,
1242, 1194, 1156, 1110, 1087, 1021, 997, 959, 925, 4.9, 7.6 Hz, 1 H, 5¢¢-H), 7.62 (d, J = 7.8 Hz, 1 H, 3¢¢-H), 7.81 (s, 1 H, 3-H),
883, 808, 779, 753, 652, 623, 596, 510
7.95 (dt, J = 1.8, 7.7 Hz, 1 H, 4¢¢-H), 8.67 (ddd, J = 0.8, 1.6, 4.9 Hz, 1 H, 6¢¢-
+
H), 9.77 (br s, 2 H, NH2 )
13C NMR: 21.3, 36.9, 44.8, 48.7, 51.2, 111.4, 125.0, 125.3, 140.0, 140.6,
141.9, 146.5, 150.0, 163.0
Synthesis 2010, No. 19, 3363–3373 © Thieme Stuttgart · New York

3368
D. Žerovnik et al.
PAPER
Table 2 Spectral Data for Compounds 2–5, 9–11 and 13 (continued)
Compd IR (cm–1) NMR (d, ppm)a
3c
3450, 3424, 2950, 2870, 2791, 2616, 2478, 2438,
1717, 1555, 1493, 1458, 1408, 1371, 1301, 1279,
1H NMR: 1.66 (tdd, J = 6.9, 7.4, 12.8 Hz, 1 H, 4¢¢-Ha), 2.03 (dtd, J = 5.5, 7.8,
12.8 Hz, 1 H, 4¢¢-Hb), 2.58 (br sept., J = 7.0 Hz, 1 H, 3¢¢-H), 2.96 (br s, 2 H,
1232, 1190, 1157, 1130, 1109, 1080, 1029, 992, 941, CHCH2N), 3.07 (br s, 2 H, 1¢-CH2), 3.35–3.43 (m, 2 H, 2¢-CH2), 3.50 (dd,
902, 865, 807, 787, 751, 710, 652, 609, 542, 459, 414 J = 5.8, 8.8 Hz, 1 H, 2¢¢-Ha), 3.64 (q, J = 7.6 Hz, 1 H, 5¢¢-Ha), 3.72 (dd,
J = 6.3, 7.4 Hz, 1 H, 5¢¢-Hb), 3.74 (s, 3 H, 1-CH3), 3.77 (t, J = 8.7 Hz, 1 H, 2¢¢-
+
Hb), 3.89 (s, 3 H, OCH3), 7.81 (s, 1 H, 3-H), 9.21 (br s, 2 H, NH2 )
13C NMR: 21.0, 29.9, 35.9, 36.8, 45.0, 49.2, 51.0, 66.7, 70.4, 111.2, 139.9,
142.0, 163.0
3d
3e
3f
3437, 3172, 2828, 2797, 2739, 2701, 2597, 2506,
2459, 2334, 2055, 1704, 1598, 1564, 1500, 1460,
1435, 1395, 1374, 1339, 1299, 1282, 1249, 1186,
1166, 1130, 1110, 1079, 1059, 1023, 981, 949, 924,
890, 810, 795, 777, 745, 705, 655, 543, 511, 467
1H NMR: 1.26 [d, J = 6.5 Hz, 6 H, (CH3)2CH], 3.00–3.10 (m, 2 H, 1¢-CH2),
3.30–3.40 [m, 3 H, CH(CH3)2 and 2¢-CH2], 3.77 (s, 3 H, 1-CH3), 3.89 (s, 3 H,
+
OCH3), 7.81 (s, 1 H, 3-H), 9.21 (br s, 2 H, NH2 )
3470, 2992, 2951, 2927, 2845, 2807, 2751, 2663,
2615, 2477, 2360, 1964, 1905, 1824, 1713, 1634,
1595, 1557, 1502, 1454, 1440, 1413, 1379, 1306,
1258, 1230, 1196, 1096, 1029, 972, 918, 877, 808,
783, 757, 744, 698, 653, 593, 492, 441
1H NMR: 3.05–3.13 (m, 2 H, 1¢-CH2), 3.28–3.36 (m, 2 H, 2¢-CH2), 3.80 (s,
3 H, OCH3), 4.09 (br s, 2 H, CH2Ph), 7.39–7.44 (m, 3 H, 3H of Ph), 7.44–7.54
(m, 4 H, 4H of Ph), 7.56–7.61 (m, 3 H, 3H of Ph), 8.08 (s, 1 H, 3-H), 9.33 (br
+
s, 2 H, NH2 )
3418, 2984, 2945, 2831, 2604, 2570, 2466, 2407,
2013, 1958, 1702, 1634, 1560, 1495, 1454, 1414,
1375, 1311, 1269, 1105, 1070, 1005, 975, 933, 874, H), 7.51 (dd, J = 2.0, 7.4 Hz, 1 H, 3¢¢-H), 7.51–7.54 (m, 1 H, p-PhH), 7.55–
810, 777, 700, 623, 598, 486, 444
1H NMR: 3.17–3.25 (m, 2 H, 1¢-CH2), 3.33–3.41 (m, 2 H, 2¢-CH2), 3.81 (s,
3 H, OCH3), 4.29 (br s, 2 H, CH2Py), 7.47 (ddd, J = 1.0, 5.0, 7.5 Hz, 1 H, 5¢¢-
7.61 (m, 4 H, o,m-PhH), 7.92 (dt, J = 1.8, 7.7 Hz, 1 H, 4¢¢-H), 8.08 (s, 1 H, 3-
+
H), 8.62 (ddd, J = 0.9, 1.6, 4.9 Hz, 1 H, 6¢¢-H), 9.64 (br s, 2 H, NH2 )
3g
3455, 3088, 2947, 2852, 2767, 2704, 2607, 2434,
1715, 1595, 1548, 1499, 1458, 1434, 1404, 1242,
1092, 1043, 972, 910, 772, 693
1H NMR: 1.59 (tdd, J = 6.9, 7.6, 12.6 Hz, 1 H, 4¢¢-Ha), 1.98 (dtd, J = 5.4, 7.9,
12.8 Hz, 1 H, 4¢¢-Hb), 2.49 (br sept., J = 7.0 Hz, 1 H, 3¢¢-H), 2.87 (br s, 2 H,
CHCH2N), 3.10 (br s, 2 H, 1¢-CH2), 3.26–3.35 (m, 2 H, 2¢-CH2), 3.42 (dd,
J = 5.9, 8.8 Hz, 1 H, 2¢¢-Ha), 3.61 (q, J = 7.7 Hz, 1 H, 5¢¢-Ha), 3.71 (t, J = 8.5
Hz, 1 H, 2¢¢-Hb), 3.73 (dd, J = 7.0, 8.1 Hz, 1 H, 5¢¢-Hb), 3.83 (s, 3 H, OCH3),
+
7.52–7.65 (m, 5 H, PhH), 8.09 (s, 1 H, 3-H), 9.10 (br s, 2 H, NH2 )
13C NMR: 21.6, 29.8, 35.7, 44.8, 48.9, 51.4, 66.7, 70.3, 112.5, 126.0, 129.3,
129.6, 138.0, 141.4, 142.6, 163.0
3h
3418, 2963, 2833, 2711, 2601, 2457, 2052, 1711,
1595, 1556, 1497, 1462, 1438, 1404, 1300, 1256,
1213, 1188, 1134, 1087, 1065, 1001, 966, 809, 772, (m, 5 H, PhH), 8.09 (s, 1 H, 3-H), 8.98 (br s, 2 H, NH2 )
1H NMR: 1.18 [d, J = 6.5 Hz, 6 H, (CH3)2CH], 3.02–3.11 (m, 2 H, 1¢-CH2),
3.15–3.33 [m, 3 H, 2¢-CH2 and CH(CH3)2], 3.83 (s, 3 H, OCH3), 7.52–7.64
+
694, 656, 616, 503, 463
13C NMR: 18.3, 22.0, 41.3, 48.8, 51.4, 112.5, 126.0, 129.2, 129.6, 138.0,
141.5, 142.6, 163.0
3i
3j
3422, 3129, 2955, 2772, 2701, 2363, 1868, 1724,
1645, 1582, 1549, 1499, 1472, 1436, 1391, 1298,
1237, 1192, 1151, 1098, 1032, 878, 802, 781, 737,
702, 608, 490, 458
1H NMR: 1.62 (s, 9 H, t-Bu), 3.05–3.18 (m, 2 H, 1¢-CH2), 3.56–3.64 (m, 2 H,
2¢-CH2), 3.73 (s, 3 H, OCH3), 4.22 (br t, J = 5.9 Hz, 2 H, CH2Ph), 7.40–7.49
(m, 3 H, o,p-PhH), 7.58–7.63 (m, 2 H, p-PhH), 7.79 (s, 1 H, 3-H), 9.77 (br s,
+
2 H, NH2 )
3453, 2948, 2776, 2479, 1707, 1549, 1464, 1437,
1400, 1374, 1277, 1238, 1215, 1150, 1098, 1046,
984, 933, 868, 810, 781, 615, 470
1H NMR: 1.65 (s, 9 H, t-Bu), 1.69 (tdd, J = 6.9, 7.6, 12.4 Hz, 1 H, 4¢¢-Ha),
2.06 (dtd, J = 5.4, 7.9, 12.4 Hz, 1 H, 4¢¢-Hb), 2.61 (br sept., J = 7.1 Hz, 1 H,
3¢¢-H), 3.01 (br s, 2 H, CHCH2N), 3.10 (br s, 2 H, 1¢-CH2), 3.51 (dd, J = 5.9,
8.8 Hz, 1 H, 2¢¢-Ha), 3.55–3.63 (m, 2 H, 2¢-CH2), 3.65 (q, J = 7.7 Hz, 1 H, 5¢¢-
Ha), 3.71–3.81 (m, 2 H, 2¢¢-Hb and 5¢¢-Hb), 3.77 (s, 3 H, OCH3), 7.80 (s, 1 H,
+
3-H), 9.40 (br s, 2 H, NH2 )
3k
4a
3439, 2972, 2949, 2833, 2801, 2740, 2698, 2648,
2597, 2569, 2507, 2458, 2327, 2052, 1710, 1587,
1553, 1467, 1442, 1400, 1373, 1298, 1275, 1238,
1H NMR: 1.28 [d, J = 6.5 Hz, 6 H, (CH3)2CH], 1.65 (s, 9 H, t-Bu), 3.09 (m,
2 H, 1¢-CH2), 3.29–3.41 [m, 1 H, CH(CH3)2], 3.50–3.59 (m, 2 H, 2¢-CH2),
+
3.77 (s, 3 H, OCH3), 7.80 (s, 1 H, 3-H), 9.19 (br s, 2 H, NH2 )
1211, 1152, 1099, 1052, 1028, 1009, 981, 945, 925, 13C NMR: 18.4, 22.9, 30.1, 42.2, 49.0, 51.1, 61.3, 112.9, 138.4, 141.5, 163.1
866, 828, 810, 781, 769, 740, 613, 555, 529, 467
3445, 3426, 3102, 3026, 2949, 2921, 2434, 1915,
1792, 1653, 1552, 1526, 1479, 1453, 1422, 1361,
1336, 1288, 1231, 1159, 1067, 1045, 1028, 1002,
980, 936, 903, 862, 800, 772, 748, 702, 671, 645,
614, 554, 489, 469, 453
1H NMR: 2.94 (t, J = 6.9 Hz, 2 H, 7-CH2), 3.50 (t, J = 6.9 Hz, 2 H, 6-CH2),
3.74 (s, 3 H, 1-CH3), 4.61 (s, 2 H, CH2Ph), 7.22–7.36 (m, 5 H, PhH), 7.69 (s,
1 H, 3-H)
13C NMR: 21.0, 36.1, 45.8, 49.0, 113.9, 127.5, 128.1, 128.7, 137.8, 138.0,
142.8, 162.9
Synthesis 2010, No. 19, 3363–3373 © Thieme Stuttgart · New York

PAPER
Pyrazole Analogues of Histamine
3369
Table 2 Spectral Data for Compounds 2–5, 9–11 and 13 (continued)
Compd IR (cm–1)
NMR (d, ppm)a
4b
3414, 3105, 2951, 2911, 1642, 1591, 1530, 1480, 1423, 1H NMR: 2.99 (t, J = 6.9 Hz, 2 H, 7-CH2), 3.64 (t, J = 6.9 Hz, 2 H, 6-CH2),
1346, 1326, 1294, 1234, 1167, 1045, 1003, 932, 885, 3.76 (s, 3 H, 1-CH3), 4.70 (s, 2 H, CH2Py), 7.23–7.29 (m, 2 H, 3¢-H and 5¢-H),
822, 762, 670, 637, 610, 567, 492, 467
7.68 (s, 1 H, 3-H), 7.75 (dt, J = 1.8, 7.7 Hz, 1 H, 4¢-H), 8.50 (dd, J = 1.7, 5.3
Hz, 1 H, 6¢-H)
13C NMR: 21.1, 36.1, 46.9, 51.4, 113.9, 122.4, 122.5, 136.9, 138.1, 143.0,
149.3, 157.9, 162.9
4c
3458, 3437, 2934, 2868, 2417, 1714, 1637, 1531,
1485, 1452, 1325, 1292, 1232, 1069, 984, 907, 708, 1 H, 4¢-Hb), 2.53 (br sept., J = 6.7 Hz, 1 H, 3¢¢-H), 2.95 (t, J = 6.9 Hz, 2 H, 7-
671
1H NMR: 1.55 (br sext., J = 6.6 Hz, 1 H, 4¢-Ha), 1.90 (br sext., J = 6.6 Hz,
CH2), 3.33–3.47 (m, 3 H, CHCH2N and 2¢¢-Ha), 3.59 (t, J = 6.8 Hz, 2 H, 6-
CH2), 3.61 (q, J = 7.6 Hz, 1 H, 5¢¢-Ha), 3.68 (br t, J = 7.9 Hz, 1 H, 5¢¢-Hb),
3.72–3.81 (m, 1 H, 2¢¢-Hb), 3.75 (s, 3 H, 1-CH3), 7.63 (s, 1 H, 3-H)
13C NMR: 20.3, 29.5, 35.8, 37.9, 46.3, 47.2, 66.8, 70.5, 113.2, 136.5, 143.6,
162.0
4d
4e
4f
3442, 2965, 1634, 1531, 1464, 1427, 1363, 1305,
1241, 1216, 1175, 1126, 1069, 1040, 985, 876, 800, CH2), 3.44 (t, J = 6.8 Hz, 2 H, 6-CH2), 3.75 (s, 3 H, 1-CH3), 4.75 [sept.,
770, 681, 634, 502, 476, 438
1H NMR: 1.09 [d, J = 6.8 Hz, 6 H, (CH3)2CH], 2.90 (t, J = 6.8 Hz, 2 H, 7-
J = 6.8 Hz, 1 H, CH(CH3)2], 7.61 (s, 1 H, 3-H)
13C NMR: 21.6, 29.9, 36.2, 42.7, 52.8, 114.9, 139.8, 142.7, 162.5
3469, 3087, 2947, 2916, 1834, 1655, 1597, 1558,
1506, 1450, 1421, 1354, 1329, 1298, 1261, 1236,
1156, 1115, 1076, 999, 969, 923, 770, 732, 696, 616, 7.51–7.64 (m, 4 H, o,m-PhH), 8.01 (s, 1 H, 3-H)
1H NMR: 3.14 (t, J = 6.8 Hz, 2 H, 7-CH2), 3.52 (t, J = 6.8 Hz, 2 H, 6-CH2),
4.66 (s, 2 H, CH2Ph), 7.23–7.38 (m, 5 H, PhH), 7.40–7.48 (m, 1 H, p-PhH),
573, 528, 502, 473, 415
3416, 3063, 2932, 1656, 1590, 1560, 1508, 1425,
1300, 1238, 1151, 1115, 1057, 989, 964, 920, 766,
692, 540, 500, 477
1H NMR: 3.19 (t, J = 6.8 Hz, 2 H, 7-CH2), 3.67 (t, J = 6.8 Hz, 2 H, 6-CH2),
4.75 (s, 2 H, CH2Py), 7.28 (ddd, J = 1.0, 4.9, 7.4 Hz, 1 H, 5¢¢-H), 7.33 (br d,
J = 7.8 Hz, 1 H, 3¢¢-H), 7.42–7.48 (tt, J = 1.4, 7.1 Hz, 1 H, p-PhH), 7.53–7.65
(m, 4 H, o,m-PhH), 7.77 (dt, J = 1.8, 7.7 Hz, 1 H, 4¢-H), 8.00 (s, 1 H, 3-H),
8.52 (ddd, J = 0.9, 1.7, 4.8 Hz, 1 H, 6¢-H)
4g
4h
3441, 3063, 2967, 2926, 2870, 1965, 1735, 1645,
1598, 1562, 1509, 1473, 1456, 1415, 1366, 1317,
1298, 1256, 1241, 1211, 1184, 1163, 1109, 1082,
1065, 1001, 968, 899, 868, 766, 739, 694, 651, 633, 2 H, 6-CH2), 3.63 (br q, J = 7.5 Hz, 1 H, 5¢¢-Ha), 3.71 (dd, J = 6.9, 8.3 Hz,
602, 544, 501, 475, 413
1H NMR: 1.58 (tdd, J = 6.7, 7.6, 12.3 Hz, 1 H, 4¢¢-Ha), 1.93 (dtd, J = 5.5, 7.5,
12.3 Hz, 1 H, 4¢¢-Hb), 2.55 (br sept., J = 7.0 Hz, 1 H, 3¢¢-H), 3.15 (t, J = 6.8
Hz, 2 H, 7-CH2), 3.36–3.52 (m, 3 H, CHCH2N and 2¢¢-Ha), 3.62 (t, J = 6.8 Hz,
1 H, 5¢¢-Hb), 3.77 (dt, J = 5.1, 8.1 Hz, 1 H, 2¢¢-Hb), 7.41–7.49 (m, 1 H, p-
PhH), 7.53–7.65 (m, 4 H, o,m-PhH), 7.95 (s, 1 H, 3-H)
3488, 2970, 2928, 2361, 1643, 1598, 1555, 1506,
1458, 1415, 1366, 1304, 1266, 1221, 1184, 1105,
1060, 978, 800, 766, 692, 644
1H NMR: 1.12 [d, J = 6.8 Hz, 6 H, (CH3)2CH], 3.11 (t, J = 6.7 Hz, 2 H, 7-
CH2), 3.47 (t, J = 6.7 Hz, 2 H, 6-CH2), 4.79 [sept., J = 6.8 Hz, 1 H,
CH(CH3)2], 7.41–7.48 (m, 1 H, p-PhH), 7.52–7.63 (m, 4 H, o,m-PhH), 7.94 (s,
1 H, 3-H)
4i
4j
3487, 2978, 2930, 1649, 1543, 1501, 1449, 1398,
1368, 1329, 1230, 1157, 1078, 1030, 989, 934, 864, Hz, 2 H, 6-CH2), 4.61 (s, 2 H, CH2Ph), 7.22–7.36 (m, 5 H, PhH), 7.69 (s, 1 H,
818, 768, 730, 702
1H NMR: 1.55 (s, 9 H, t-Bu), 3.17 (t, J = 6.8 Hz, 2 H, 7-CH2), 3.46 (t, J = 6.8
3-H)
3465, 3083, 2982, 2585, 2060, 1974, 1674, 1616,
1570, 1514, 1462, 1401, 1358, 1296, 1238, 1201,
1180, 1041, 1002, 876, 814, 767, 463
1H NMR: 1.58 (s, 9 H, t-Bu), 3.32 (t, J = 6.8 Hz, 2 H, 7-CH2), 3.73 (t, J = 6.5
Hz, 2 H, 6-CH2), 4.95 (s, 2 H, CH2Py), 7.25–7.31 (m, 2 H, 3¢¢-H and 5¢¢-H),
7.70 (s, 1 H, 3-H), 8.42 (dt, J = 1.5, 7.9 Hz, 1 H, 4¢¢-H), 8.80 (dd, J = 0.7, 5.6
Hz, 1 H, 6¢¢-H)
13C NMR: 23.8, 29.5, 30.2, 46.8, 47.5, 60.4, 113.9, 125.6, 135.7, 141.2, 142.9,
146.3, 153.5, 163.0
4k
3493, 2974, 2931, 2865, 2361, 1645, 1542, 1503,
1397, 1369, 1328, 1287, 1228, 1158, 1068, 1040,
993, 907, 863, 770, 673
1H NMR: 1.55 (tdd, J = 6.8, 7.6, 12.3 Hz, 1 H, 4¢¢-Ha), 1.56 (s, 9 H, t-Bu),
1.91 (dtd, J = 5.5, 7.8, 12.2 Hz, 1 H, 4¢¢-Hb), 2.52 (br sept., J = 7.0 Hz, 1 H,
3¢¢-H), 3.18 (t, J = 6.8 Hz, 2 H, 7-CH2), 3.33–3.46 (m, 3 H, CHCH2N and 2¢¢-
Ha), 3.55 (t, J = 6.6 Hz, 2 H, 6-CH2), 3.61 (br q, J = 7.5 Hz, 1 H, 5¢¢-Ha), 3.69
(dd, J = 7.0, 8.3 Hz, 1 H, 5¢¢-Hb), 3.75 (dt, J = 5.6, 8.3 Hz, 1 H, 2¢¢-Hb), 7.63
(s, 1 H, 3-H)
13C NMR: 23.8, 29.4, 29.5, 37.8, 46.4, 47.1, 60.1, 66.8, 70.5, 114.7, 135.5,
141.9, 162.2
4l
3472, 3417, 2975, 2934, 1639, 1545, 1500, 1442,
1396, 1366, 1301, 1220, 1185, 1156, 1070, 1031,
995, 866, 826, 800, 770, 731, 624, 482
1H NMR: 1.09 [d, J = 6.8 Hz, 6 H, (CH3)2CH], 1.56 (s, 9 H, t-Bu), 3.14 (t,
J = 6.7 Hz, 2 H, 7-CH2), 3.41 (t, J = 6.7 Hz, 2 H, 6-CH2), 4.73 [sept., J = 6.8
Hz, 1 H, CH(CH3)2], 7.62 (s, 1 H, 3-H)
Synthesis 2010, No. 19, 3363–3373 © Thieme Stuttgart · New York

3370
D. Žerovnik et al.
PAPER
Table 2 Spectral Data for Compounds 2–5, 9–11 and 13 (continued)
Compd IR (cm–1) NMR (d, ppm)a
5a
5b
5c
9
3209, 3078, 2945, 2876, 1660, 1629, 1530, 1487,
1H NMR (CDCl3): 2.90 (t, J = 6.8 Hz, 2 H, 7-CH2), 3.62 (dt, J = 2.6, 6.8 Hz,
1451, 1421, 1354, 1292, 1244, 1196, 1030, 987, 932, 2 H, 6-CH2), 3.83 (s, 3 H, CH3), 6.08 (br s, 1 H, NH), 7.87 (s, 1 H, 3-H)
897, 785, 688
3235, 3067, 1667, 1633, 1549, 1513, 1457, 1427,
1265, 979, 783, 765
1H NMR: 3.06 (t, J = 6.8 Hz, 2 H, 7-CH2), 3.42 (dt, J = 2.5, 6.8 Hz, 2 H, 6-
CH2), 7.38 (br s, 1 H, NH), 7.46 (t, J = 7.3 Hz, 1 H, p-PhH), 7.52–7.64 (m,
4 H, o,m-PhH), 7.95 (s, 1 H, 3-H)
3307, 3221, 3104, 3067, 2980, 1662, 1545, 1503,
1426, 1397, 1367, 1298, 1238, 1161, 1117, 995, 794, (dt, J = 2.6, 6.8 Hz, 2 H, 6-CH2), 6.19 (br s, 1 H, NH), 7.87 (s, 1 H, 3-H)
683
1H NMR (CDCl3): 1.65 (s, 9 H, t-Bu), 3.13 (t, J = 6.8 Hz, 2 H, 7-CH2), 3.59
2977, 2933, 1748, 1713, 1692, 1454, 1414, 1366,
1246, 1167, 876, 701
1H NMR (CDCl3): 1.47 (br s, 9 H, t-Bu), 2.56 (br s, 2 H, 2-CH2), 3.46 (br s,
2 H, 3-CH2), 4.46 (s, 2 H, CH2Ph), 7.18–7.36 (m, 5 H, Ph)
13C NMR: 28.6, 33.5, 42.8, 50.8, 80.5, 127.5, 127.7, 128.7, 138.3, 155.9,
177.4
10
2978, 2932, 1735, 1696, 1476, 1455, 1416, 1367,
1248, 1163, 1121, 1028, 872, 735, 700
1H NMR (CDCl3): 1.46 (br s, 9 H, t-Bu), 2.78 (br s, 2 H, 4-CH2), 3.41 (br s,
4 H, 2-CH2, 5-CH2), 3.71 (s, 3 H, OCH3), 4.44 (s, 2 H, CH2Ph), 7.18–7.36 (m,
5 H, PhH)
13C NMR (CDCl3): 28.4, 41.9, 49.1, 50.6, 51.5, 52.3, 80.0, 127.3, 127.8,
128.6, 138.4, 155.6, 167.4, 201.4
11
13
3415, 2940, 2784, 2733, 2409, 1748, 1712, 1600,
1438, 1402, 1364, 1330, 1256, 1188, 1102, 1028,
986, 861, 750, 695
1H NMR: 3.07 (br s, 4 H, 2-CH2, 4-CH2), 3.64 (s, 3 H, OCH3), 3.68 (br s, 2 H,
5-CH2), 4.12 (br s, 2 H, CH2Ph), 7.39–7.47 (m, 3 H, o,p-PhH), 7.52–7.59 (m,
+
2 H, m-PhH), 9.39 (br s, 2 H, NH2 )
3466, 3061, 3028, 2963, 2927, 2866, 2812, 1658,
1599, 1479, 1437, 1420, 1372, 1286, 1232, 1202,
1137, 1095, 1039, 1005, 987, 866, 764, 745, 701
1H NMR (CDCl3): 2.46 (t, J = 6.4 Hz, 2 H, 5-CH2), 3.19 and 3.30 [2 × s, 1:1,
6 H, N(CH3)2], 3.33 (t, J = 6.3 Hz, 2 H, 6-CH2), 4.68 (s, 2 H, CH2Ph), 7.20–
7.37 (m, 5 H, PhH), 8.03 (s, 1 H, 3¢-H)
13C NMR: 37.3, 42.1, 43.3, 47.5, 49.3, 100.1, 126.6, 127.1, 127.9, 137.6,
158.4, 166.2, 190.6
a Recorded in DMSO-d6 unless noted.
Reductive Alkylation of Primary Amines 2; General Proce-
dures
1-Substituted Methyl 5-[2-(Alkylamino)ethyl]-1H-pyrazole-4-
carboxylate Hydrochlorides 3a–i, 3k, and 3l, and 1-tert-Butyl-5-
[(pyridin-2-yl)methyl]-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-
c]pyridin-4-one Hydrochloride (4j)
Melting points were determined with a Kofler micro hot stage appa-
ratus. The NMR spectra were obtained with a Bruker Avance DPX
300 spectrometer at 300 MHz for 1H and 75.5 MHz for 13C nuclei,
using DMSO-d6 or CDCl3 as solvent with TMS as internal standard.
Mass spectra were recorded with a Q-TOF Premier spectrometer,
IR spectra with a Perkin–Elmer Spectrum BX FTIR spectrophotom-
eter. Microanalyses were performed on a Perkin–Elmer CHN Anal-
yser 2400 II. Column chromatography was performed on silica gel
(Fluka, Silica gel 60, particle size 0.035–0.070 mm).
General Procedure A
A mixture of amine dihydrochloride 2 (5 mmol), anhydrous MeOH
(40 mL), and anhydrous NaOAc (820 mg, 10 mmol) was stirred at
r.t. for 5 min. AcOH (605 mg, 578 mL, 10 mmol) and benzaldehyde
(800 mg, 765 mL, 7.5 mmol) or pyridine-2-carbaldehyde (811 mg,
721 mL, 7.5 mmol) were added and the mixture was cooled to 0 °C
(ice-bath). Then, NaBH4 (191 mg, 5 mmol) was added portion-wise
and the stirring at 0 °C was continued for 4 h. The reaction mixture
was evaporated in vacuo and the semi-solid residue was purified by
column chromatography (EtOH–EtOAc, 20%). Fractions contain-
ing the product were combined and evaporated in vacuo and the res-
idue was dissolved in Et2O (50 mL). HCl in Et2O (3 M, 5 mL, 15
mmol) was added and the mixture was stirred for 5 min. The precip-
itate was collected by filtration to give 3. Compounds 3a, 3b, 3e, 3f,
3i and 4j were prepared in this manner. Experimental, physical and
analytical data for these compounds are given in Table 1; spectral
data are given in Table 2.
Pyridine-2-carbaldehyde, tetrahydrofuran-2-carbaldehyde (50%
aqueous solution), methylhydrazine, phenylhydrazine, and tert-bu-
tylhydrazine are commercially available (Sigma–Aldrich). Methyl
5-[2-(tert-butoxycarbonylamino)ethyl]-1-(tert-butyl)-1H-pyrazole-
4-carboxylate, methyl 5-(2-aminoethyl)-1-methyl-1H-pyrazole-4-
carboxylate dihydrochloride (2a), and methyl 5-(2-aminoethyl)-1-
phenyl-1H-pyrazole-4-carboxylate dihydrochloride (2b) were pre-
pared according to literature procedures.11
Methyl 5-(2-Aminoethyl)-1-tert-butyl-1H-pyrazole-4-carboxy-
late Hydrochloride (2c)
HCl in EtOAc (2 M, 30 mL, 60 mmol) was added to a stirred mix-
ture of methyl 5-[2-(tert-butoxycarbonylamino)ethyl]-1-tert-butyl-
1H-pyrazole-4-carboxylate11 (3.25 g, 10 mmol), anhydrous EtOH
(5 mL) and EtOAc (10 mL) at 0 °C, and the mixture was stirred at
0 °C for 30 min then at r.t. for 2 h. The precipitate was collected by
filtration, washed with EtOAc (2 × 20 mL), and dried in vacuo at r.t.
over NaOH pellets for 12 h to give 2c. Experimental, physical, and
analytical data for compound 2c are given in Table 1; spectral data
are given in Table 2.
General Procedure B
A mixture of amine dihydrochloride 2 (5 mmol), MeOH (40 mL),
4-methylmorpholine (200 mL, 184 mg, 1.8 mmol), tetrahydrofuran-
3-carboxaldehyde (50% in H2O; 1.33 g, 1.20 mL, 6.5 mmol) or ace-
tone (10 mL, excess), and 10% Pd–C (150 mg) was hydrogenated
(3 bar of H2) at r.t. for 8 h. The catalyst was removed by filtration
Synthesis 2010, No. 19, 3363–3373 © Thieme Stuttgart · New York

PAPER
Pyrazole Analogues of Histamine
3371
through a fritted funnel and washed with MeOH (2 × 5 mL). The
combined filtrate was evaporated in vacuo and the residue was trit-
urated with EtOAc (20 mL). The precipitate was collected by filtra-
tion and washed with EtOAc (10 mL) to give 3. Compounds 3c, 3d,
3g, 3h, 3k and 3l were prepared in this manner. Experimental, phys-
ical, and analytical data for these compounds are given in Table 1;
spectral data are given in Table 2.
Methyl5-[Benzyl(tert-butoxycarbonyl)amino]-3-oxopentanoate
(10)
Under Ar, 1,1¢-carbonyldiimidazole (CDI; 3.06 g, 18.9 mmol) was
added to a solution of 9 (4.33 g, 15.5 mmol) in anhydrous THF (60
mL) and the mixture was stirred at r.t. for 2 h. A solid mixture of
anhydrous MgCl2 (1.43 g, 15 mmol) and potassium monomethyl
malonate (3.63 g, 23.2 mmol) was added under Ar in one portion via
a powder funnel, which was rinsed with anhydrous THF (20 mL),
and the mixture was stirred under Ar at r.t. for 20 h. Volatile com-
ponents were evaporated in vacuo, EtOAc (200 mL) was added to
the residue and the resulting suspension was washed with aq
NaHSO4 (1 M, 2 × 70 mL) and brine (70 mL). The organic phase
was dried over anhydrous Na2SO4, filtered, and the filtrate was
evaporated in vacuo. The residue was purified by column chroma-
tography (silica gel; EtOAc–hexanes, 50%). Fractions containing
the product were combined and volatile components were evaporat-
ed in vacuo to give 10, which was used for further transformations
without purification. Experimental, physical, and analytical data for
compound 10 are given in Table 1; spectral data are given in
Table 2.
Cyclisation of Methyl 5-(2-Aminoethyl)-1H-pyrazole-4-carbox-
ylates 2 and Their N-Alkyl Analogues 3; General Procedures
Synthesis of 1,5,6,7-Tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-
ones 4 and 5
Preparation of Compounds 4; General Procedure
A mixture of 3 (1 mmol), 1-propanol (15 mL), and t-BuOK (560
mg, 5 mmol) was stirred under reflux for 15 h. Volatile components
were evaporated in vacuo and the residue was purified by column
chromatography (EtOH–EtOAc, 20%). Fractions containing the
product were combined and evaporated in vacuo to give 4. Com-
pounds 4a–i, 4k and 4l were prepared in this manner. Experimental,
physical, and analytical data for these compounds are given in
Table 1; spectral data are given in Table 2.
N-Benzyl-5-methoxy-3,5-dioxopentan-1-aminium Chloride (11)
The crude compound 10 (5.03 g, 15 mmol) was dissolved in ethere-
al HCl (3.6 M; 50 mL) and the mixture was stirred at r.t. for 12 h.
The precipitate was collected by filtration and washed with anhy-
drous Et2O (3 × 20 mL) to give 11. Experimental, physical, and an-
alytical data for compound 11 are given in Table 1; spectral data are
given in Table 2.
Preparation of Compounds 5; General Procedure
A mixture of 2 (1 mmol), DMF (5 mL) and Et3N (3.5 mL) was
stirred at reflux for 5 h. Volatile components were evaporated in
vacuo and the residue was purified by column chromatography
(EtOH–EtOAc, 20%). Fractions containing the product were com-
bined and evaporated in vacuo. The residue was triturated with Et2O
(4 mL) and the precipitate was collected by filtration to give 5. Ex-
perimental, physical, and analytical data for compounds 5a–c are
given in Table 1; spectral data are given in Table 2.
1-Benzylpiperidine-2,4-dione (12)
Aq NaOH (2 M; 2.5 mL, 25 mmol) was added to a solution of 11
(3.26 g, 12 mmol) in H2O (60 mL), the mixture was stirred at r.t. for
1 h, and acidified with aq HCl (1 M) to pH ~4. The product was ex-
tracted with CH2Cl2 (3 × 50 mL), the organic phases were com-
bined, dried over anhydrous Na2SO4, filtered, and the filtrate was
evaporated in vacuo to give 12. Physical and spectral data for com-
pound 12 were consistent with the literature data.13
Synthesis of Compounds 4a, 4e and 4i by Benzylation of 4H-
pyrazolo[4,3-c]pyridin-4-ones 5a–c; General Procedure
t-BuOK (112 mg, 1 mmol) was added to a solution of 5 (0.5 mmol)
in DMF (2 mL) and the mixture was stirred at r.t. for 15 min. BnBr
(100 mL, 144 mg, 0.83 mmol) was added and stirring at r.t. was con-
tinued for 12 h. The reaction mixture was poured into 10% aq.
AcOH (10 mL) and the product was extracted with EtOAc (30 mL).
The organic phase was washed with H2O (3 × 50 mL), dried over
anhydrous Na2SO4, filtered, and the filtrate was evaporated in vac-
uo. The residue was purified by column chromatography (EtOAc–
hexanes, 67% then EtOH–EtOAc, 20%). Fractions containing the
product were combined and volatile components were evaporated
in vacuo to give 4. Experimental, physical, and analytical data for
compounds 4a, 4e and 4i are given in Table 1; spectral data are giv-
en in Table 2.
1-Benzyl-3-[(dimethylamino)methylidene]piperidine-2,4-dione
(13)
DMFDMA (2.24 g, 2.50 mL, 18.8 mmol) was added to a solution
of 12 (2.03 g, 10 mmol) in anhydrous toluene (20 mL) and the re-
sulting reaction mixture was stirred at r.t. for 12 h. Volatile compo-
nents were evaporated in vacuo and the residue was purified by
column chromatography (EtOH–EtOAc, 10%). Fractions contain-
ing the product were combined and volatile components were evap-
orated in vacuo to give 13, which was used for further
transformations without purification. Experimental, physical, and
analytical data for compound 13 are given in Table 1; spectral data
are given in Table 2.
N-Benzyl-N-tert-butoxycarbonyl-b-alanine (9)
DBU (150 mg, 150 mL, ~1 mmol) was added to a mixture of benzyl-
amine (2.14 g, 2.18 mL, 20 mmol) and methyl acrylate (6; 1.74 g,
1.82 mL, 20 mmol), and the resulting mixture was stirred at r.t. for
12 h to give 7. MeCN (40 mL) and Boc2O (4.40 g, 20 mmol) were
added, the reaction mixture was stirred at r.t. for 24 h, and volatile
components were evaporated in vacuo to give 8. The crude com-
pound 8 was dissolved in MeOH (40 mL), aq NaOH (2 M, 30 mL,
60 mmol) was added, and the mixture was stirred at r.t. for 3 h. The
reaction mixture was carefully acidified while stirring: first with aq
HCl (6 M, 10 mL, 60 mmol) and then with aq NaHSO4 (1 M, 30 mL,
30 mmol). The product was extracted with EtOAc (2 × 100 mL), the
combined organic phases were dried over anhydrous Na2SO4, fil-
tered, and the filtrate was evaporated in vacuo to give 9, which was
used for further transformations without purification. Experimental,
physical, and analytical data for compound 9 are given in Table 1;
spectral data are given in Table 2.
Synthesis of 1-Substituted 5-Benzyl-1,5,6,7-tetrahydro-4H-
pyrazolo[4,3-c]pyridin-4-ones 4a, 4e and 4i from Enaminone
13; General Procedure
A mixture of 13 (129 mg, 0.5 mmol), monosubstituted hydrazine
hydrochloride (0.5 mmol), and 2-methoxyethanol (5 mL) was
stirred at r.t. for 0.5 h and then at reflux for 2 h. Volatile components
were evaporated in vacuo and the residue was purified by column
chromatography (EtOAc). Fractions containing the product were
combined and volatile components were evaporated in vacuo. The
residue was triturated with either Et2O (3 mL, for 4a and 4e) or a
mixture of Et2O and n-hexane (1:1; 3 mL, for 4i), and the precipitate
was collected by filtration to give 4. Experimental, physical, and
analytical data for compounds 4a, 4e and 4i are given in Table 1;
spectral data are given in Table 2.
Synthesis 2010, No. 19, 3363–3373 © Thieme Stuttgart · New York

3372
D. Žerovnik et al.
PAPER
X-ray Structure Analysis
(2) (a) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.;
Lubell, W. D. Tetrahedron 1997, 53, 12789. (b) Cluzeau,
J.; Lubell, W. D. Biopolymers 2005, 80, 98. (c)Maison,W.;
Prenzel, A. H. G. P. Synthesis 2005, 1031. (d) Vagner, J.;
Qu, H.; Hruby, V. J. Curr. Opin. Chem. Biol. 2008, 12, 292;
and references cited therein.
(3) (a) Patrick, G. L. In An Introduction to Medicinal
Chemistry, 3rd ed.; Oxford University Press: Oxford, 2005.
(b) Kazuta, Y.; Hirano, K.; Natsume, K.; Yamada, S.;
Kimura, R.; Matsumoto, S.-i.; Furuichi, K.; Matsuda, A.;
Shuto, S. J. Med. Chem. 2003, 46, 1980. (c) Liebscher, J.;
Patzel, M. Synlett 1994, 471.
(4) (a) Paillet-Loilier, M.; Fabis, F.; Lepailleur, A.; Bureau, R.;
Butt-Gueulle, S.; Dauphin, F.; Lesnard, A.; Delarue, C.;
Vaudry, H.; Rault, S. Bioorg. Med. Chem. Lett. 2007, 17,
3018. (b) Pullagurla, M.; Dukat, M.; Roth, B. L.; Setola, V.;
Glennon, R. A. Med. Chem. Res. 2005, 14, 1.
(5) (a) Elguero, J. Pyrazoles, In Comprehensive Heterocyclic
Chemistry II, Vol. 3; Katritzky, A. R.; Rees, C. W.; Scriven,
E. F. V., Eds.; Elsevier Science Ltd.: Oxford, 1996, 1.
(b) Stanovnik, B.; Svete, J. Pyrazoles, In Science of
Synthesis, Houben-Weyl Methods of Organic
Single crystal X-ray diffraction data of compounds 4a and 4i
(Table 3) were collected at r.t. on a Nonius Kappa CCD diffracto-
meter (Mo-Ka radiation) using the Nonius Collect Software.18
DENZO and SCALEPACK19 were used for indexing and scaling of
the data. The structures were solved by means of SIR97.20 Refine-
ment was performed using the Xtal3.421 program package and the
crystallographic plots were prepared with ORTEP III.22 Crystal
structures were refined on F values using the full-matrix least-
squares procedure. The non-hydrogen atoms were refined anisotro-
pically in both cases, while the positions of hydrogen atoms were
geometrically calculated; their positional and isotropic atomic dis-
placement parameters were not refined. Absorption correction was
not necessary. Regina23 weighting scheme was used in both cases.
Table 3 X-ray Crystal Data for Compounds 4a and 4i24
Compound
Formula
4a
4i
C14H15N3O
C17H21N3O
Mr
241.29
283.38
Crystal system
Space group
a (Å)
monoclinic
P21/a
monoclinic
P21/a
Transformations, Vol. 12; Neier, R., Ed.; Georg Thieme
Verlag: Stuttgart, 2002, 15.
(6) (a) Svete, J. In (4R*,5R*)-4-Benzoylamino-5-phenyl-3-
pyrazolidinone – A Useful Building Block in the Synthesis
of Functionalized Pyrazoles, In Stereochemistry Research
Trends; Horvat, M. A.; Golob, J. H., Eds.; Nova Science
Publishers, Inc.: New York, 2008, 129; open access
item: https://www.novapublishers.com/catalog/
12.6263(2)
7.47630(10)
13.7210(3)
108.8110(11)
1226.05(4)
4
11.0738(2)
10.1626(2)
14.3918(2)
102.1287(10)
1583.48(5)
4
b (Å)
c (Å)
product_info.php?products_id=16416. (b) Pezdirc, L.;
Stanovnik, B.; Svete, J. Aust. J. Chem. 2009, 62, 1661; and
references cited therein.
b (°)
V (Å3)
(7) (a) Stanovnik, B.; Svete, J. Chem. Rev. 2004, 104, 2433.
(b) Svete, J. ARKIVOC 2006, (vii), 35; and the references
cited therein.
Za
r (Mg m–3)
m (mm–1)
Crystal shape
Dimensions (mm)
Threshold criterion
Final R and Rw
1.307
1.189
(8) Baškovč, B.; Bevk, D.; Stanovnik, B.; Svete, J. J. Comb.
Chem. 2009, 11, 500; and references cited therein.
(9) Kralj, D.; Grošelj, U.; Meden, A.; Dahmann, G.; Stanovnik,
B.; Svete, J. Tetrahedron 2007, 63, 11213.
(10) Kralj, D.; Novak, A.; Dahmann, G.; Grošelj, U.; Meden, A.;
Svete, J. J. Comb. Chem. 2008, 10, 664.
(11) Kralj, D.; Friedrich, M.; Grošelj, U.; Kiraly-Potpara, S.;
Meden, A.; Wagger, J.; Dahmann, G.; Stanovnik, B.; Svete,
J. Tetrahedron 2009, 65, 7151.
(12) Verardo, G.; Geatti, P.; Pol, E.; Giumanini, A. G. Can. J.
Chem. 2002, 80, 779.
0.085
0.076
white plate
0.27 × 0.22 × 0.07
I > 2.0s(I)
0.051, 0.044
white plate
0.25 × 0.20 × 0.10
I > 2.0s(I)
0.052, 0.034
a Z: Multiplicity of the space group.
(13) (a) Takano, S.; Yuta, K.; Hatakeyama, S.; Ogasawara, K.
Tetrahedron Lett. 1979, 369. (b) Ibenmoussa, S.;
Chavignon, O.; Teulade, J.-C.; Viols, H.; Debouzy, J.-C.;
Chapat, J.-P.; Gueiffier, A. Heterocycl. Commun. 1998, 4,
317. (c) Chang, D.; Feiten, H.-J.; Witholt, B.; Li, Z.
Tetrahedron: Asymmetry 2002, 13, 2141. (d) Asahi, K.;
Nishino, H. Heterocycl. Commun. 2005, 11, 379.
(e) Asahia, K.; Nishino, H. Tetrahedron 2005, 61, 11107.
(14) (a) Yeom, C.-E.; Kim, M. J.; Kim, B. M. Tetrahedron 2007,
63, 904. (b) Gill, H. S.; Freeman, S.; Irwin, W. J.; Wilson, K.
A. Eur. J. Med. Chem. 1996, 31, 847. (c) Chen, X. S.; Jin, S.
Z.; Wu, J.; Zhang, P. Synthesis 2008, 3931.
Acknowledgment
We acknowledge with thanks the financial support from Boehrin-
ger-Ingelheim Pharma GmbH & Co. KG (Biberach, Germany). The
financial support from the Slovenian Research Agency through
grant P1–0179 is gratefully acknowledged.
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Synthesis 2010, No. 19, 3363–3373 © Thieme Stuttgart · New York

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Pyrazole Analogues of Histamine
3373
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Synthesis 2010, No. 19, 3363–3373 © Thieme Stuttgart · New York