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Synthesis 2010(19): 3363-3373  
DOI: 10.1055/s-0030-1257864
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© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of 1,5,6,7-Tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-ones as Conformationally Constrained Pyrazole Analogues of Histamine

Darja Žerovnika, Uroš Grošelja, David Kralja, Črt Malavašiča, Jure Bezenšeka, Georg Dahmannb, Katarina Starea, Anton Medena, Branko Stanovnika, Jurij Svete*a
a Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, P.O. Box 537, 1000 Ljubljana, Slovenia
b Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Chemical Research, 88397 Biberach, Germany
Fax: +386(1)2419220; e-Mail: jurij.svete@fkkt.uni-lj.si;

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Received 21 April 2010
Publication Date:
22 July 2010 (online)

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Synthesis of 1,5,6,7-Tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-ones as Conformationally Constrained Pyrazole Analogues of HistamineSynthesis 2010; 2010(19): e4-e4
DOI: 10.1055/s-0030-1258257

Abstract

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).

Key words

enaminones - cyclisation - alkylation - pyrazolo[4,3-c]pyridine - histamine

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 proteins. [¹] [²] Because of the crucial role of histamine, tyramine, dopamine, tryptamine, serotonin and melatonin (Figure  [¹] ) as chemical messengers in biological processes, the preparation of novel synthetic analogues based on the 2-(heteroaryl)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 various synthetic options available for the construction of the pyrazole ring, two classical approaches are most frequently employed. The first is based on a cyclocondensation reaction 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]

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-benzoylamino-5-phenyl-3-pyrazolidinone-derived azometh­ine imines to various dipolarophiles, [6] and (b) cyclo-condensation of functionalised enaminones with monosubstituted hydrazines. [7] In particular, β-(dimethylamino)-enones, which are stable β-keto aldehyde analogues, have found use as versatile reagents in heterocyclic synthesis including combinatorial applications. [8] Within this context, we recently reported a simple four-step synthesis of 1-substituted 4-(2-aminoethyl)-1H-pyrazol-5-ols as pyrazole analogues of histamine. [9] Soon after, a one-pot, parallel, 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 related pyrazole analogues of histamine analogues. [¹¹] In an extension of this study, we found some intriguing further transformations of the above histamine analogues. Namely, 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 analogues of histamine. Herein, we report the results of our study on the synthesis of 1,5-disubstituted 1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-ones 4, as novel and conformationally constrained histamine analogues.

Figure 1

First, we undertook the synthesis of the title compounds 4 via δ-amino esters 2 as the key intermediates. Compounds 2a and 2b were prepared in four steps from commercially available Boc-β-alanine (1) following a literature procedure. [¹¹] In the same manner, the novel compound 2c was also obtained in 86% yield by acidolytic deprotection of its known Boc-derivative. [¹¹] Two methods were studied for the preparation of title compounds: alkylation of the primary amino group followed by base-catalysed lactamisation (method A), and base-catalysed lactamisation followed 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-carbaldehyde 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 surprisingly, compounds 3a-i,k,l were more reluctant to cyclise, 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] ).

Scheme 1 Synthesis of 4 by methods A and B. Reagents and conditions: (i) benzaldehyde or pyridine-2-carbaldehyde, NaBH4, MeOH, AcOH, 0 ˚C→r.t. (procedure A [¹²] ); (ii) tetrahydrofuran-3-carbalde­hyde 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 δ-amino esters 2 were first cyclised to the 5-unsubstituted pyrazolo[4,3-c]pyridin-4-ones 5, followed by N-alkylation. The δ-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 bromide and potassium tert-butoxide in N,N-dimethylform­amide then furnished compounds 4a, 4e and 4i in moderate yields (Scheme  [¹] , Method B, Table  [¹] ).

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, tolu­ene, r.t.; (viii) R³NHNH2˙HCl, 2-methoxyethanol, r.t.→reflux.

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). Solvent-free 1,8-diazabicyclo[5.4.0]undec-7-ene-catalysed Michael addition of benzylamine to methyl acrylate (6) gave the N-benzyl-β-alanine ester (7), [¹4] which was treated with Boc2O. The so-formed methyl N-benzyl-β-alaninate (8) [¹5] was hydrolysed with aqueous sodium hydroxide to give 9 [¹6] 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 condensation [¹7] of the crude product 9 with magnesium monomethyl malonate was performed according to the procedure described previously for homologation of closely related Boc-β-alanine [¹¹] and gave β-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-dimethyl­formamide dimethylacetal (DMFDMA) followed by cyclocondensation of the so-formed enamino ketone 13 with hydrazines. Thus, treatment of 12 with DMFDMA in anhydrous toluene at room temperature gave the enamino-derivative 13 in 88% yield. Subsequent cyclisation of 13 with methylhydrazine, phenylhydrazine or tert-butylhydrazine was carried out in 2-methoxyethanol at reflux to furnish the desired pyrazolo[4,3-c]pyridin-4-ones 4a,e,i in 79-87% yield (Scheme  [²] , Table  [¹] ).

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. Compounds 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] 9 [¹6] and 12 [¹³] were in agreement with data reported in the literature. Intermediates 7 [¹4] and 8 [¹5] were not isolated in pure form and were characterised only by ¹H NMR analysis. Additional characterisation data for known compound 9 [¹6] 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-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-ones 4 as novel, conformationally constrained pyrazole analogues of histamine were synthesised. Three complementary synthetic methods were developed. Methods A and B are six-step syntheses starting from Boc-β-alanine (1), which is transformed in four steps into the key intermediates 2 according to the procedure reported previously. [¹¹] From this point on, two complementary synthetic pathways are feasible: (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]piperidine-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 histamine analogues 4 with variable substituents at N(1) and N(5). Each of the N-substituents can be introduced at different stages of the synthesis, while three different types of common reagents (aldehydes and ketones, alkyl halides, and primary amines) can be employed for the introduction of the N(5)-substituent.

Table 1 Experimental Data for Compounds 2-5, 9-11 and 13 (continued)
Compd R¹ R² Proc. Yield (%) Mp (˚C) Molecular formula, analysis data ESI-MS (m/z),
HRMS
2c t-Bu - - 86 173-179 C11H19N3O2˙HCl
Calcd.: C, 50.40; H, 7.70; N, 16.05
Found: C, 50.04; H, 7.89; N; 16.18 		226 [M + H]+
Calcd.: 226.1556
Found: 226.1547
3a Me

A 22 183-188 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
3b Me

A 47 123-127 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
3c Me

B 73 141-144 C13H21N3O3˙1HCl
Calcd.: C, 50.64; H, 7.23; N, 13.63
Found: C, 50.69; H, 7.45; N, 13.47 		268 [M + H]+
Calcd.: 268.1661
Found:268.1660
3d Me

B 33 220-225 C11H19N3O2˙HCl
Calcd.: C, 50.48; H, 7.70; N, 16.05
Found: C, 50.10; H, 7.79; N, 15.84 		226 [M + H]+
3e Ph

A 52 176-180 C20H21N3O2˙HCl
Calcd.: C, 64.60; H, 5.96; N, 11.30
Found: C, 64.65; H, 6.08; N, 11.38 		336 [M + H]+
3f Ph

A 47 166-174 C19H20N4O2˙2HCl
Calcd.: C, 55.75; H, 5.42; N, 13.69
Found: C, 55.71; H, 5.69; N, 13.51 		337 [M + H]+
3g Ph

B 63 148-155 C18H23N3O3˙1HCl
Calcd.: C, 58.37; H, 6.56; N, 11.34
Found: C, 58.28; H, 6.84; N, 11.30 		330 [M + H]+
Calcd.: 330.1818
Found: 330.1810
3h Ph

B 80 209-213 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
3i t-Bu

A 44 176-180 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]+
3j a t-Bu

A - - - -
3k t-Bu

B 54 172-177 C16H27N3O3˙HCl
Calcd.: C, 55.56; H, 8.16; N, 12.15
Found: C, 55.57; H, 8.28; N, 12.10 		310 [M + H]+
3l t-Bu

B 43 188-194 C14H25N3O2˙1 HCl
Calcd.: C, 54.53; H, 8.54; N, 13.63
Found: C, 54.71; H, 8.75; N, 13.74 		268 [M + H]+
Calcd.: 268.2025
Found: 268.2023
4a Me

- 72b
36c
79d 		 97-100 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
4b Me

- 45 111-114 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
4c Me

- 54 oil C12H17N3O2 236 [M + H]+
Calcd.: 236.1399
Found: 236.1400
4d Me

- 52  72-75 C10H15N3O
 194 [M + H]+
Calcd.: 194.1293
Found: 194.1285
4e Ph

- 89b
49c
86d 		136-138 C19H17N3O
Calcd.: C, 75.23; H, 5.65; N, 13.85
Found: C, 75.06; H, 5.76; N, 13.80 		304 [M + H]+
4f Ph

- 66  95-99 C18H16N4O
Calcd.: C, 71.04; H, 5.30; N, 18.41
Found: C, 70.62; H, 5.23; N, 18.32 		305 [M + H]+
4g Ph

- 77  79-83 C17H19N3O2
Calcd.: C, 68.67; H, 6.44; N, 14.13
Found: C, 68.76; H, 6.46; N, 14.02 		298 [M + H]+
4h Ph

- 17 212-217 C15H17N3O
Calcd.: C, 70.56; H, 6.71; N, 16.46
Found: C, 70.50; H, 6.81; N, 16.55 		256 [M + H]+
4i t-Bu

- 92b
38c
87d 		 77-79 C17H21N3O
Calcd.: C, 72.06; H, 7.47; N, 14.83
Found: C, 71.85; H, 7.37; N, 14.85 		284 [M + H]+
4j t-Bu

- 22 136-143 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
4k t-Bu

- 81 oil C15H23N3O2 278 [M + H]+
Calcd.: 278.1869
Found: 278.1870
 4l t-Bu

- 70 135-138 C13H21N3O
Calcd.: C, 66.35; H, 8.99; N, 17.86
Found: C, 66.75; H, 9.21; N, 17.85 		236 [M + H]+
 5a Me - - 45 197-200 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
 5b Ph - - 66 202-205 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
 5c t-Bu - - 51 164-166 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
 9 - - - 79 oil C15H21NO4 278 [M - H]+
Calcd.: 278.1392
Found: 278.1396
10 - - - 70 oil C18H25NO5 358 [M + Na]+
Calcd.: 358.1644
Found: 358. 1630
11 - - - 93 141-148 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
13 - - - 83 oil C15H18N2O2 259 [M + H]+
Calcd.: 259.1447
Found: 259.1443
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 (continued)
Compd IR (cm-¹) NMR (δ, 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, 1147, 1097, 1027, 980, 931, 894, 806, 780, 746, 700, 625, 594, 536, 501, 424 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, CH 2Ph), 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), 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, 1242, 1194, 1156, 1110, 1087, 1021, 997, 959, 925, 883, 808, 779, 753, 652, 623, 596, 510 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, CH 2Py), 7.49 (ddd, J = 1.0, 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), 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
3c 3450, 3424, 2950, 2870, 2791, 2616, 2478, 2438, 1717, 1555, 1493, 1458, 1408, 1371, 1301, 1279, 1232, 1190, 1157, 1130, 1109, 1080, 1029, 992, 941, 902, 865, 807, 787, 751, 710, 652, 609, 542, 459, 414 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, CHCH 2N), 3.07 (br s, 2 H, 1′-CH2), 3.35-3.43 (m, 2 H, 2′-CH2), 3.50 (dd, 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 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, (CH 3)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 +)
3e 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, CH 2Ph), 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 +)
3f 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, 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, CH 2Py), 7.47 (ddd, J = 1.0, 5.0, 7.5 Hz, 1 H, 5′′-H), 7.51 (dd, J = 2.0, 7.4 Hz, 1 H, 3′′-H), 7.51-7.54 (m, 1 H, p-PhH), 7.55-7.61 (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, CHCH 2N), 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, 694, 656, 616, 503, 463 ¹H NMR: 1.18 [d, J = 6.5 Hz, 6 H, (CH 3)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 (m, 5 H, PhH), 8.09 (s, 1 H, 3-H), 8.98 (br s, 2 H, NH2 +)
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 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, CH 2Ph), 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 +)
3j 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, CHCH 2N), 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 3439, 2972, 2949, 2833, 2801, 2740, 2698, 2648, 2597, 2569, 2507, 2458, 2327, 2052, 1710, 1587, 1553, 1467, 1442, 1400, 1373, 1298, 1275, 1238, 1211, 1152, 1099, 1052, 1028, 1009, 981, 945, 925, 866, 828, 810, 781, 769, 740, 613, 555, 529, 467 ¹H NMR: 1.28 [d, J = 6.5 Hz, 6 H, (CH 3)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 +)
¹³C NMR: 18.4, 22.9, 30.1, 42.2, 49.0, 51.1, 61.3, 112.9, 138.4, 141.5, 163.1
4a 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, CH 2Ph), 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
4b 3414, 3105, 2951, 2911, 1642, 1591, 1530, 1480, 1423, 1346, 1326, 1294, 1234, 1167, 1045, 1003, 932, 885, 822, 762, 670, 637, 610, 567, 492, 467 ¹H NMR: 2.99 (t, J = 6.9 Hz, 2 H, 7-CH2), 3.64 (t, J = 6.9 Hz, 2 H, 6-CH2), 3.76 (s, 3 H, 1-CH3), 4.70 (s, 2 H, CH 2Py), 7.23-7.29 (m, 2 H, 3′-H and 5′-H), 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, 671 ¹H NMR: 1.55 (br sext., J = 6.6 Hz, 1 H, 4′-Ha), 1.90 (br sext., J = 6.6 Hz, 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-CH2), 3.33-3.47 (m, 3 H, CHCH 2N 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 3442, 2965, 1634, 1531, 1464, 1427, 1363, 1305, 1241, 1216, 1175, 1126, 1069, 1040, 985, 876, 800, 770, 681, 634, 502, 476, 438 ¹H NMR: 1.09 [d, J = 6.8 Hz, 6 H, (CH 3)2CH], 2.90 (t, J = 6.8 Hz, 2 H, 7-CH2), 3.44 (t, J = 6.8 Hz, 2 H, 6-CH2), 3.75 (s, 3 H, 1-CH3), 4.75 [sept., 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
4e 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, 573, 528, 502, 473, 415 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, CH 2Ph), 7.23-7.38 (m, 5 H, PhH), 7.40-7.48 (m, 1 H, p-PhH), 7.51-7.64 (m, 4 H, o,m-PhH), 8.01 (s, 1 H, 3-H)
4f 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, CH 2Py), 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 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, 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, CHCH 2N and 2′′-Ha), 3.62 (t, J = 6.8 Hz, 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, 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)
4h 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, (CH 3)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 3487, 2978, 2930, 1649, 1543, 1501, 1449, 1398, 1368, 1329, 1230, 1157, 1078, 1030, 989, 934, 864, 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 Hz, 2 H, 6-CH2), 4.61 (s, 2 H, CH 2Ph), 7.22-7.36 (m, 5 H, PhH), 7.69 (s, 1 H, 3-H)
4j 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, CH 2Py), 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, CHCH 2N 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, (CH 3)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)
 5a 3209, 3078, 2945, 2876, 1660, 1629, 1530, 1487, 1451, 1421, 1354, 1292, 1244, 1196, 1030, 987, 932, 897, 785, 688 ¹H NMR (CDCl3): 2.90 (t, J = 6.8 Hz, 2 H, 7-CH2), 3.62 (dt, J = 2.6, 6.8 Hz, 2 H, 6-CH2), 3.83 (s, 3 H, CH3), 6.08 (br s, 1 H, NH), 7.87 (s, 1 H, 3-H)
 5b 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)
 5c 3307, 3221, 3104, 3067, 2980, 1662, 1545, 1503, 1426, 1397, 1367, 1298, 1238, 1161, 1117, 995, 794, 683 ¹H NMR (CDCl3): 1.65 (s, 9 H, t-Bu), 3.13 (t, J = 6.8 Hz, 2 H, 7-CH2), 3.59 (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)
 9 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, CH 2Ph), 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, CH 2Ph), 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 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, CH 2Ph), 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 +)
13 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, CH 2Ph), 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-d 6 unless noted.

Melting points were determined with a Kofler micro hot stage apparatus. 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-d 6 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 spectrophotometer. Microanalyses were performed on a Perkin-Elmer CHN Analyser 2400 II. Column chromatography was performed on silica gel (Fluka, Silica gel 60, particle size 0.035-0.070 mm).

Pyridine-2-carbaldehyde, tetrahydrofuran-2-carbaldehyde (50% aqueous solution), methylhydrazine, phenylhydrazine, and tert-butylhydrazine 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 prepared according to literature procedures. [¹¹]

Methyl 5-(2-Aminoethyl)-1- tert -butyl-1 H -pyrazole-4-carboxylate Hydrochloride (2c)

HCl in EtOAc (2 M, 30 mL, 60 mmol) was added to a stirred mixture of methyl 5-[2-(tert-butoxycarbonylamino)ethyl]-1-tert-butyl-1H-pyrazole-4-carboxylate [¹¹] (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] .

Reductive Alkylation of Primary Amines 2; General Procedures1-Substituted Methyl 5-[2-(Alkylamino)ethyl]-1 H -pyrazole-4-carboxylate Hydrochlorides 3a-i, 3k, and 3l, and 1- tert -Butyl-5-[(pyridin-2-yl)methyl]-1,5,6,7-tetrahydro-4 H -pyrazolo[4,3- c ]pyridin-4-one Hydrochloride (4j)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 µL, 10 mmol) and benzaldehyde (800 mg, 765 µL, 7.5 mmol) or pyridine-2-carbaldehyde (811 mg, 721 µL, 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 containing the product were combined and evaporated in vacuo and the residue 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 precipitate 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] .

General Procedure B

A mixture of amine dihydrochloride 2 (5 mmol), MeOH (40 mL), 4-methylmorpholine (200 µL, 184 mg, 1.8 mmol), tetrahydrofuran-3-carboxaldehyde (50% in H2O; 1.33 g, 1.20 mL, 6.5 mmol) or ace­tone (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 through a fritted funnel and washed with MeOH (2 × 5 mL). The combined filtrate was evaporated in vacuo and the residue was triturated with EtOAc (20 mL). The precipitate was collected by filtration and washed with EtOAc (10 mL) to give 3. Compounds 3c, 3d, 3g, 3h, 3k and 3l 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] .

Cyclisation of Methyl 5-(2-Aminoethyl)-1 H -pyrazole-4-carboxylates 2 and Their N -Alkyl Analogues 3; General ProceduresSynthesis of 1,5,6,7-Tetrahydro-4 H -pyrazolo[4,3- c ]pyridin-4-ones 4 and 5Preparation 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. Compounds 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] .

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 combined and evaporated in vacuo. The residue was triturated with Et2O (4 mL) and the precipitate was collected by filtration to give 5. Experimental, physical, and analytical data for compounds 5a-c are given in Table  [¹] ; spectral data are given in Table  [²] .

Synthesis of Compounds 4a, 4e and 4i by Benzylation of 4 H -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 µL, 144 mg, 0.83 mmol) was added and stirring at r.t. was continued 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 vacuo. 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 given in Table  [²] .

N -Benzyl- N - tert -butoxycarbonyl-β-alanine (9)

DBU (150 mg, 150 µL, ˜1 mmol) was added to a mixture of benzyl­amine (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 compound 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, filtered, 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] .

Methyl 5-[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 components 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 chromatography (silica gel; EtOAc-hexanes, 50%). Fractions containing the product were combined and volatile components were evaporated 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] .

N -Benzyl-5-methoxy-3,5-dioxopentan-1-aminium Chloride (11)

The crude compound 10 (5.03 g, 15 mmol) was dissolved in ethereal 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 anhydrous Et2O (3 × 20 mL) to give 11. Experimental, physical, and analytical data for compound 11 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 extracted with CH2Cl2 (3 × 50 mL), the organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was evaporated in vacuo to give 12. Physical and spectral data for compound 12 were consistent with the literature data. [¹³]

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 resulting reaction mixture was stirred at r.t. for 12 h. Volatile components were evaporated in vacuo and the residue was purified by column chromatography (EtOH-EtOAc, 10%). Fractions containing the product were combined and volatile components were evaporated 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] .

Synthesis of 1-Substituted 5-Benzyl-1,5,6,7-tetrahydro-4 H -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] .

X-ray Structure Analysis

Single crystal X-ray diffraction data of compounds 4a and 4i (Table  [³] ) were collected at r.t. on a Nonius Kappa CCD diffractometer (Mo-Kα radiation) using the Nonius Collect Software. [¹8] DENZO and SCALEPACK [¹9] were used for indexing and scaling of the data. The structures were solved by means of SIR97. [²0] Refinement was performed using the Xtal3.4 [²¹] 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 anisotropically in both cases, while the positions of hydrogen atoms were geometrically calculated; their positional and isotropic atomic displacement parameters were not refined. Absorption correction was not necessary. Regina [²³] weighting scheme was used in both cases.

Table 3 X-ray Crystal Data for Compounds 4a and 4i [²4]
Compound 4a 4i
Formula C14H15N3O C17H21N3O
Mr 241.29 283.38
Crystal system monoclinic monoclinic
Space group P21/a P21/a
a (Å) 12.6263(2) 11.0738(2)
b (Å) 7.47630(10) 10.1626(2)
c (Å) 13.7210(3) 14.3918(2)
β (˚) 108.8110(11) 102.1287(10)
V (ų) 1226.05(4) 1583.48(5)
Z a 4 4
ρ (Mg m-³) 1.307 1.189
µ (mm-¹) 0.085 0.076
Crystal shape white plate white plate
Dimensions (mm) 0.27 × 0.22 × 0.07 0.25 × 0.20 × 0.10
Threshold criterion I > 2.0σ(I) I > 2.0σ(I)
Final R and R w 0.051, 0.044 0.052, 0.034
a Z: Multiplicity of the space group.

Acknowledgment

We acknowledge with thanks the financial support from Boehringer-Ingelheim Pharma GmbH & Co. KG (Biberach, Germany). The financial support from the Slovenian Research Agency through grant P1-0179 is gratefully acknowledged.

    References

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24

Crystallographic data (excluding structure factors) for the structures in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 770933 (4a) and CCDC 770934 (4i). These data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/conts/retrieving.html.

    References

  • 1a Wells JA. McClendon CL. Nature (London)  2007,  450:  1001 
    Search in Google Scholar
  • 1b Lee GM. Craik CS. Science (Washington, D.C.)  2009,  324:  213 
    Search in Google Scholar
  • 1c Robinson JA. DeMarco S. Gombert F. Moehle K. Obrecht D. Drug Discovery Today  2008,  13:  944 
    Search in Google Scholar
  • 2a Hanessian S. McNaughton-Smith G. Lombart H.-G. Lubell WD. Tetrahedron  1997,  53:  12789 
    Search in Google Scholar
  • 2b Cluzeau J. Lubell WD. Biopolymers  2005,  80:  98 
    Search in Google Scholar
  • 2c Maison W. Prenzel AHGP. Synthesis  2005,  1031 
  • 2d Vagner J. Qu H. Hruby VJ. Curr. Opin. Chem. Biol.  2008,  12:  292 ; and references cited therein
    Search in Google Scholar
  • 3a Patrick GL. In An Introduction to Medicinal Chemistry   3rd ed.:  Oxford University Press; Oxford: 2005. 
    Search in Google Scholar
  • 3b 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 
    Search in Google Scholar
  • 3c Liebscher J. Patzel M. Synlett  1994,  471 
  • 4a 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 
    Search in Google Scholar
  • 4b Pullagurla M. Dukat M. Roth BL. Setola V. Glennon RA. Med. Chem. Res.  2005,  14:  1 
    Search in Google Scholar
  • 5a Elguero J. Pyrazoles, In Comprehensive Heterocyclic Chemistry II   Vol. 3:  Katritzky AR. Rees CW. Scriven EFV. Elsevier Science Ltd.; Oxford: 1996.  p.1 
    Search in Google Scholar
  • 5b Stanovnik B. Svete J. Pyrazoles, In Science of Synthesis, Houben-Weyl Methods of Organic Transformations   Vol. 12:  Neier R. Georg Thieme Verlag; Stuttgart: 2002.  p.15 
    Search in Google Scholar
  • 6a 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 MA. Golob JH. Nova Science Publishers, Inc.; New York: 2008.  p.129 ; open access item: https://www.novapublishers.com/catalog/product_info.php?products_id=16416
  • 6b Pezdirc L. Stanovnik B. Svete J. Aust. J. Chem.  2009,  62:  1661 ; and references cited therein
    Search in Google Scholar
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    Search in Google Scholar
  • 7b Svete J. ARKIVOC  2006,  (vii):  35 ; and the references cited therein
    Search in Google Scholar
  • 8 Baškovč B. Bevk D. Stanovnik B. Svete J. J. Comb. Chem.  2009,  11:  500 ; and references cited therein
    CrossrefSearch in Google Scholar
  • 9 Kralj D. Grošelj U. Meden A. Dahmann G. Stanovnik B. Svete J. Tetrahedron  2007,  63:  11213 
    CrossrefSearch in Google Scholar
  • 10 Kralj D. Novak A. Dahmann G. Grošelj U. Meden A. Svete J. J. Comb. Chem.  2008,  10:  664 
    CrossrefSearch in Google Scholar
  • 11 Kralj D. Friedrich M. Grošelj U. Kiraly-Potpara S. Meden A. Wagger J. Dahmann G. Stanovnik B. Svete J. Tetrahedron  2009,  65:  7151 
    CrossrefSearch in Google Scholar
  • 12 Verardo G. Geatti P. Pol E. Giumanini AG. Can. J. Chem.  2002,  80:  779 
    CrossrefSearch in Google Scholar
  • 13a Takano S. Yuta K. Hatakeyama S. Ogasawara K. Tetrahedron Lett.  1979,  369 
  • 13b Ibenmoussa S. Chavignon O. Teulade J.-C. Viols H. Debouzy J.-C. Chapat J.-P. Gueiffier A. Heterocycl. Commun.  1998,  4:  317 
    Search in Google Scholar
  • 13c Chang D. Feiten H.-J. Witholt B. Li Z. Tetrahedron: Asymmetry  2002,  13:  2141 
    Search in Google Scholar
  • 13d Asahi K. Nishino H. Heterocycl. Commun.  2005,  11:  379 
    Search in Google Scholar
  • 13e Asahia K. Nishino H. Tetrahedron  2005,  61:  11107 
    Search in Google Scholar
  • 14a Yeom C.-E. Kim MJ. Kim BM. Tetrahedron  2007,  63:  904 
    Search in Google Scholar
  • 14b Gill HS. Freeman S. Irwin WJ. Wilson KA. Eur. J. Med. Chem.  1996,  31:  847 
    Search in Google Scholar
  • 14c Chen XS. Jin SZ. Wu J. Zhang P. Synthesis  2008,  3931 
  • 15 Lima PG. Sequeira LC. Costa PRR. Tetrahedron Lett.  2001,  42:  3525 
    CrossrefSearch in Google Scholar
  • 16a De Michelis C. Rocheblave L. Priem G. Chermann JC. Kraus JL. Bioorg. Med. Chem.  2000,  8:  1253 
    Search in Google Scholar
  • 16b Bezencon O, Bur D, Corminboeuf O, Grisostomi C, Remen L, Richard-Bildstein S, and Weller T. inventors; PCT Int. Appl.; WO  2007102127.  ; Chem. Abstr. 2007, 147, 365397
  • 16c Kong T. Syed S. Urwyler S. Bertrand S. Bertrand D. Reymond J.-L. ChemMedChem  2008,  3:  1520 
    Search in Google Scholar
  • 17a Brooks DW. Lu LD.-L. Masamune S. Angew. Chem.  1979,  91:  76 
    Search in Google Scholar
  • 17b Hashiguchi S. Kawada A. Natsugari H. Synthesis  1992,  403 
  • 17c Moreau RJ. Sorensen EJ. Tetrahedron  2007,  63:  6446 
    Search in Google Scholar
  • 18 Collect Software   Nonius BV. Delft; The Netherlands: 1998. 
  • 19 Otwinowski Z. Minor W. Methods Enzymol.  1997,  276:  307 
    PubMedSearch in Google Scholar
  • 20 Altomare A. Burla MC. Camalli M. Cascarano GL. Giacovazzo C. Guagliardi A. Moliterni AGG. Polidori G. Spagna R. J. Appl. Crystallogr.  1999,  32:  115 
    CrossrefSearch in Google Scholar
  • 21 Hall SR. King GSD. Stewart JM. The Xtal3.4 User’s Manual   University of Western Australia; Lamb/Perth: 1995. 
  • 22 Wang H. Robertson BE. Structure and Statistics in Crystallography   Wilson AJC. Adenine Press; New York: 1985. 
  • 23 Burnett MN. Johnson CK. In ORTEP-III: Oak Ridge Thermal Ellipsoid Plot Program for Crystal Structure Illustrations   Oak Ridge National Laboratory Report ORNL-6895; 1996. 
24

Crystallographic data (excluding structure factors) for the structures in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 770933 (4a) and CCDC 770934 (4i). These data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/conts/retrieving.html.

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Figure 1

Scheme 1 Synthesis of 4 by methods A and B. Reagents and conditions: (i) benzaldehyde or pyridine-2-carbaldehyde, NaBH4, MeOH, AcOH, 0 ˚C→r.t. (procedure A [¹²] ); (ii) tetrahydrofuran-3-carbalde­hyde 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.

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, tolu­ene, r.t.; (viii) R³NHNH2˙HCl, 2-methoxyethanol, r.t.→reflux.