CC BY-NC-ND 4.0 · SynOpen 2020; 04(04): 71-83
DOI: 10.1055/s-0040-1707304
paper

Synthesis and Crystal Structures of 4,5-Dihydroimidazo[1,5-b]pyrazol-6-ones

,
María Vera
,
Bruno Martiz
,
Francisco Ródenas
,
,
,
Delia Bautista
The authors acknowledge the financial support of the Fundación Séneca of the Comunidad Autónoma de la Región de Murcia (project 19249/PI/14).
 


Abstract

The synthesis of previously unattainable 2,5-disubstituted 4,5-dihydroimidazo[1,5-b]pyrazol-6-ones has been developed. Electrochemical reductions of readily available 2,2,2-trichloroethylideneacetophenones were followed by reaction with hydrazine, leading to 3-aryl-5-dichloromethyl-2-pyrazolines. These were treated with isocyanates to obtain the corresponding aminocarbonyl derivatives, which were found to be able to form an otherwise almost inaccessible imidazo[1,5-b]pyrazole ring system via a one-step reaction involving internal condensation followed by hydrogen chloride elimination and aromatization. The molecular­ structures of 2-(4-methylphenyl)-5-tosyl-4,5-dihydro­imidazo[1,5-b]pyrazol-6-one, 5-dichloromethyl-N-(4-chlorophenyl)-4,5-dihydro-3-p-tolylpyrazole-1-carboxamide, and 5-(4-bromophenyl)-2-p-tolyl-4,5-dihydroimidazo[1,5-b]pyrazol-6-one were determined by X-ray crystallographic analysis.


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Recent reviews on the synthesis and properties of heterocycles condensed to a pyrazole core have reported that these are an important source of bioactive molecules.[1] [2] Imidazopyrazoles have been recognized as substances of significant chemical, biological and medicinal interest.[3,4] By far, the most well-known compounds are those pertaining to the imidazo[1,2-b]pyrazole family, which have been described as possessing noteworthy anticancer,[4] [5] [6] antibacterial,[7] [8] and anti-inflammatory[9] [10] properties, among others. 5-Aminopyrazoles, the synthetic methods for which have been extensively reviewed,[11] are the main preparative intermediates for imidazo[1,2-b]pyrazoles.[12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] The synthesis and properties of imidazo[4,5-c]pyrazoles have also received considerable attention.[30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] 5-Aminopyrazoles have also been of great utility in preparing these compounds.[32] [33] [36] [40] [41] However, synthetic methodology for obtaining imidazo[1,5-b]pyrazole derivatives is notably lacking, and very little is known about these compounds.[3] [4] Only a few individual examples having this uncommon ring fusion have been previously prepared; for example, by cyclodehydration of substituted pyrazolylmethylacetamides leading to 2,3-dihydroimidazo[1,5-b] derivatives related to cyclized histamine,[43] preparation of 2,3-dihydro-1H-imidazo[1,5-b]pyrazole-4,6(3aH,5H)-dione from 1-(benzylideneamino)-5-(2-hydroxyethyl)hydantoin,[44] and the synthesis of hexahydro-4,4-dimethyl-1,3a-diaryl-6-oxo-1H-imidazo[1,5-b]pyrazole-3-carbonitriles from α-aminoisobutyrophenone phenyl hydrazones.[45] Concerning imidazopyrazolones, studies on the synthesis, properties and usefulness of substances exhibiting [1,2-b],[46] [47] [48] [49] [50] [4,5-c],[51] [52] and [3,4-b][45] ring systems have been successful. However, the synthesis of imidazo[1,5-b]pyrazol-6-ones remains to be achieved. To our knowledge, this paper describes the first synthetic approach to this class of compounds.

In an earlier work we synthesized novel 3-aryl-5-dichloromethyl-2-pyrazolines 5 starting from chloral, a cheap multipurpose starting material for organic synthesis,[53] and inexpensive, commercially available acetophenones. 2,2,2-Trichloroethylideneacetophenones 3 and 2,2-dichlorovinylacetophenones 4 were key intermediates (Scheme [1]).[54] [55] Taking into account the specific molecular arrangement of compounds 5 – two active centers of opposite polarity and the presence of an electrophilic dichloromethyl group attached to C-5 instead of the nucleophilic amino group present in 5-aminopyrazoles – we envisaged that compounds 5 could be of key interest as they offer privileged access to still unattainable imidazo[1,5-b]pyrazol-6-ones. The results of this study are detailed here, concluding in an effective method for preparing hitherto unknown 2-aryl-5-tosyl-4,5-dihydroimidazo[1,5-b]pyrazol-6-ones 10, as displayed in Scheme [2]. Pyrazolines 5 were treated with toluenesulfonyl isocyanate to obtain the corresponding toluenesulfonylaminocarbonyl intermediates 7, which were subjected to base treatment and directly provided the desired products (Table [1]). The scope of this method could also be extended by using aryl and alkyl isocyanates, which allowed the synthesis of the target 2,5-diaryl- and 5-alkyl-2-aryl-4,5-dihydroimidazo[1,5-b]pyrazol-6-ones 12 (Table [2]). It should be noted that, because of their utility for preparing a diversity of fused heterocyclic compounds, 5-aminopyrazoles have become key reagents for organic and medicinal chemistry.[56] However, these intermediates are not able to form an imidazo[1,5-b]pyrazole ring system. Conversely, we have overcome this limitation through 5-dichloromethylpyrazolines 5. Furthermore, these appear to be promising agents offering many other possibilities to prepare a wide variety of fused heterocycles.

Zoom Image
Scheme 1 Synthesis of 5-dichloromethyl-2-pyrazolines 5 through chloral derivatives. Ar: (a) C6H5; (b) 4-ClC6H4; (c) 4-BrC6H4; (d) 4-MeC6H4; (e) 4-MeOC6H4; (f) 4-O2NC6H4; (g) 4-PhC6H4; (h) 2-C10H7; (i) 2,4-Cl2C6H3; (j) 3-BrC6H4

A series of 3-aryl-5-dichloromethyl-2-pyrazolines 5 was prepared by applying our previously reported synthetic method,[54] which involves preparation and dehydration of chloralacetophenones 2 to obtain the corresponding 2,2,2-trichloroethylideneacetophenones 3, selective electrochemical reduction[55] [57] to give dichlorovinylacetophenones 4, and treatment with hydrazine hydrate.

To investigate the first synthetic approach to products 10 through pyrazolines 5, compound 5d was selected as a model. Reaction with tosyl isocyanate led to the previously unknown 5-dichloromethyl-3-p-tolyl-N-tosyl-2-pyrazoline-1-carboxamide (7d; Ar = p-tolyl) in 96% yield (Scheme [2]). Next, a cyclization process promoted by strong bases, such as potassium tert-butoxide or lithium diisopropylamide, was attempted, but provided disappointing results, since complex mixtures of unidentifiable products were observed. However, on heating to reflux in triethylamine, the progressive formation of a single product was observed. This was isolated and spectroscopically identified as the hitherto unknown 2-(4-methylphenyl)-5-toluenesulfonyl-4,5-dihydroimidazo[1,5-b]pyrazol-6-one (10d; yield 65%), the molecular structure of which was confirmed by X-ray crystallographic analysis (Figure [1]).[58]

Zoom Image
Figure 1 X-ray crystal structure of compound 10d (thermal ellipsoids drawn at the 50% probability level)
Zoom Image
Scheme 2 Synthesis of 2-aryl-5-tosyl-4,5-dihydroimidazo[1,5-b]pyrazol-6-ones 10 from pyrazolines 5

In view of this successful result, products 10a, 10d, 10e, and 10hj were similarly obtained from their respective precursors 7 in boiling triethylamine; however, other conversions required operating at higher reaction temperature using a sealed vessel under pressure (Table [1]). Successful results were also obtained with a more rapid and efficient one-pot preparative process. Thus, mixtures of compounds 5 with toluenesulfonyl isocyanate and triethylamine were heated at 130 °C for two hours, directly providing the desired products 10 in fair to good yields (Table [1]). It is clear that the formation of these products is explicable by initial generation of intermediates 7, which, under suitable basic experimental conditions, can undergo internal attack at the dichloromethyl group, leading to intermediates 8, the chemical evolution of which would occur by hydrogen chloride elimination to give intermediates 9. Finally, these would undergo an isomerization process to give the most stable products 10 (Scheme [2]).

Table 1 Preparation of Imidazo[1,5-b]pyrazol-6-ones 10

Entry

Intermediate 7

Yield (%)*

Product 10

Yield (%)*

a

97

50a (63)c

b

92

63b (75)c

c

92

38b (57)c

d

96

65a (70)c

e

97

46a (77)c

f

93

55b (88)c

g

98

60b (68)c

h

83

78a (82)c

i

70

80b (85)c

j

80

65a (82)c

* Isolated yield

a At reflux temperature.

b At 130 °C.

c At 130 °C (one-pot process).

Once the synthesis of compounds 10 had been achieved, we focused on expanding the novel preparative method to obtain 2,5-diaryl- and 5-alkyl-2-aryl-4,5-dihydroimidazo[1,5-b]pyrazol-6-ones 12 by using aryl and alkyl isocyanates as acylating agents. Thus, reactions of a range of pyrazolines 5 with a variety of aryl and alkyl isocyanates were carried out to obtain novel derivatives 11 in moderate to good yields. The geometrical characteristics of these compounds­ were determined by X-ray crystallographic analysis of 5-dichloromethyl-N-(4-chlorophenyl)-4,5-dihydro-3-p-tolylpyrazole-1-carboxamide (11f; Figure [2]).[59]

Zoom Image
Figure 2 X-ray crystal structure of compound 11f (thermal ellipsoids drawn at the 50% probability level)

Cyclizations of intermediates 11 promoted by potassium tert-butoxide, diisopropylamide or triethylamine were ineffective. Conversely, employing DBU as base afforded good results for the targeted dihydroimidazo[1,5-b]pyrazol-6-ones 12, which were obtained in fair to good yields (Table [2]).

The molecular structure of one of these compounds: 5-(4-bromophenyl)-2-p-tolyl-4,5-dihydro-imidazo[1,5-b]-pyrazol-6-one (12h) was determined by X-ray crystallographic analysis (Figure [3]).[60]

To conclude, a new and highly flexible synthetic method for preparing imidazo[1,5-b]pyrazoles is reported that provides straightforward access to previously unattainable 4,5-dihydroimidazo[1,5-b]pyrazol-6-ones through 5-dichloro-methyl-2-pyrazolines. Given the previous scant progress in generating this type of ring fusion, these novel products are not only of high interest in themselves, but also in terms of exploring their possible biological properties. The development of syntheses for other classes of heterocyclic compounds by applying a similar strategy also appears feasible.

Table 2 Preparation of Imidazo[1,5-b]pyrazol-6-ones 12

Entry

Isocyanate

Intermediate 11

Yield (%)a

Product 12

Yield (%)a

a

50

40

b

43

70

c

51

53

d

74

70

e

70

75

f

70

83

g

72

62

h

71

64

i

63

51

j

61

54

k

60

50

a Isolated yield.

Zoom Image
Figure 3 X-ray crystal structure of compound 12h (thermal ellipsoids drawn at the 50% probability level)

NMR spectra were recorded with a Bruker AV-300 or Bruker AV-400 with tetramethylsilane as internal reference. High-resolution mass spectra (HRMS) were obtained with a time-of-flight (TOF) instrument equipped with electrospray ionization (ESI). IR spectra were recorded with Nicolet Impact 400 or Jasco FTIR-4700LE spectrophotometers. Microanalyses were performed with a Carlo Erba EA-1108 analyser. Melting points were determined with a Büchi Melting point B-540, and are uncorrected. 3-Aryl-5-dichloromethyl-2-pyrazolines 5 were prepared as previously described.[54]


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Synthesis of 7; General Procedure

To a stirred suspension of compound 5 (2.5 mmol) in anhydrous diethyl ether (10 mL), a solution of toluenesulfonyl isocyanate (2.5 mmol) in anhydrous diethyl ether (10 mL) was slowly added dropwise (ca. 1 drop per second) under a nitrogen atmosphere. The stirring was continued for 10 min at r.t., and the precipitate was collected by filtration and crystallized from the appropriate solvent.


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5-Dichloromethyl-3-phenyl-1-tosylaminocarbonyl-2-pyrazoline (7a)

Yield: 1.04 g (97%); white prisms; mp 168 °C (dec) (MeCN).

IR (Nujol): 3285, 1698, 1599, 1379, 1346, 1163, 1078, 895, 866, 848, 785, 673 cm–1.

1H NMR (CDCl3, 400 MHz): δ = 2.44 (s, 3 H), 3.51 (dd, J = 18.3, 11.3 Hz, 1 H), 3.63 (dd, J = 18.3, 5.8 Hz, 1 H), 4.88 (ddd, J = 11.3, 5.8, 2.6 Hz, 1 H), 6.41 (d, J = 2.6 Hz, 1 H), 7.35 (d, J = 8.2 Hz, 2 H), 7.43–7.50 (m, 3 H), 7.72 (dd, J = 6.3, 1.8 Hz, 2 H), 7.99 (d, J = 8.2 Hz, 2 H), 8.67 (br s, 1 H).

13C NMR (CDCl3, 100.8 MHz): δ = 21.76 (CH3), 35.15 (CH2), 63.26 (CH), 71.11 (CHCl2), 126.98 (CH), 128.42 (CH), 129.00 (CH), 129.62 (C), 129.67 (CH), 131.38 (CH), 136.04 (C), 145.00 (C), 148.41 (C=O), 155.12 (C=N).

MS: m/z (%) = 425 (0.5) [M]+, 427 (0.4) [M++2], 228 (11), 197 (12), 155 (29), 145 (100), 128 (18), 91 (70), 77 (22).

Anal. Calcd for C18H17Cl2N3O3S: C, 50.71; H, 4.02; N, 9.86; S, 7.52. Found: C, 50.83; H, 3.96; N, 9.85; S, 7.50.


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5-Dichloromethyl-3-(4-chlorophenyl)-1-tosylaminocarbonyl-2-pyrazoline (7b)

Yield: 1.06 g (92%); white needles; mp 224 °C (dec) (MeCN).

IR (Nujol): 3330, 1706, 1600, 1408, 1346, 1166, 1087, 821, 785, 664 cm–1.

1H NMR (CDCl3, 400 MHz): δ = 2.44 (s, 3 H), 3.47 (dd, J = 18.3, 11.3 Hz, 1 H), 3.59 (dd, J = 18.3, 5.8 Hz, 1 H), 4.88 (ddd, J = 11.3, 5.8, 2.6 Hz, 1 H), 6.40 (d, J = 2.6 Hz, 1 H), 7.34 (d, J = 8.3 Hz, 2 H), 7.41 (d, J = 8.6 Hz, 2 H), 7.66 (d, J = 8.6 Hz, 2 H), 7.99 (d, J = 8.3 Hz, 2 H), 8.74 (br s, 1 H).

13C NMR (CDCl3, 100.8 MHz): δ = 21.76 (CH3), 35.05 (CH2), 63.43 (CH), 71.03 (CHCl2), 128.12 (C), 128.22 (CH), 128.42 (CH), 129.30 (CH), 129.68 (CH), 135.96 (C), 137.50 (C), 145.07 (C), 148.35 (C=O), 154.00 (C=N).

MS: m/z (%) = 459 (0.2) [M]+, 461 (0.2) [M++2], 268 (10), 197 (20), 179 (100), 155 (35), 91 (77), 64 (20).

Anal. Calcd for C18H16Cl3N3O3S: C, 46.92; H, 3.50; N, 9.12; S, 6.96. Found: C, 46.90; H, 3.49; N, 9.08; S, 7.00.


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3-(4-Bromophenyl)-5-dichloromethyl-1-tosylaminocarbonyl-2-pyrazoline (7c)

Yield: 1.16 g (92%); white needles; mp 231 °C (dec) (MeCN).

IR (Nujol): 3331, 1706, 1593, 1404, 1347, 1166, 1072, 1009, 821, 784, 666 cm–1.

1H NMR (CDCl3, 300 MHz): δ = 2.44 (s, 3 H), 3.47 (dd, J = 18.3, 11.1 Hz, 1 H), 3.59 (dd, J = 18.3, 6.0 Hz, 1 H), 4.88 (ddd, J = 11.1, 6.0, 2.4 Hz, 1 H), 6.40 (d, J = 2.4 Hz, 1 H), 7.58 (m, 4 H), 7.34 (d, J = 8.5 Hz, 2 H), 7.99 (d, J = 8.5 Hz, 2 H), 8.75 (br s, 1 H).

13C NMR (CDCl3, 75.4 MHz): δ = 21.76 (CH3), 35.00 (CH2), 63.46 (CH), 71.03 (CHCl2), 125.90 (C), 128.38 (CH), 128.42 (CH), 128.57 (C), 129.69 (CH), 132.26 (CH), 135.98 (C), 145.08 (C), 148.35 (C=O), 154.09 (C=N).

MS: m/z (%) = 503 (0.15) [M]+, 505 (0.18) [M++2], 306 (7), 308 (11), 223 (85), 225 (77), 197 (34), 155 (61), 144 (82), 91 (100), 65 (32).

Anal. Calcd for C18H16BrCl2N3O3S: C, 42.79; H, 3.19; N, 8.32; S, 6.35. Found: C, 42.81; H, 3.26; N, 8.30; S, 6.30.


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5-Dichloromethyl-3-(4-methylphenyl)-1-tosylaminocarbonyl-2-pyrazoline (7d)

Yield: 1.06 g (96%); white prisms; mp 203 °C (dec) (MeCN).

IR (Nujol): 3293, 1696, 1350, 1168, 1072, 852, 782, 734, 668 cm–1.

1H NMR (CDCl3, 400 MHz): δ = 2.40 (s, 3 H), 2.44 (s, 3 H), 3.48 (dd, J = 18.3, 11.2 Hz, 1 H), 3.59 (dd, J = 18.3, 5.6 Hz, 1 H), 4.85 (ddd, J = 11.2, 5.6, 2.3 Hz, 1 H), 6.41 (d, J = 2.3 Hz, 1 H), 7.25 (d, J = 7.8 Hz, 2 H), 7.34 (d, J = 8.1 Hz, 2 H), 7.61 (d, J = 7.8 Hz, 2 H), 7.99 (d, J = 8.1 Hz, 2 H), 8.71 (br s, 1 H).

13C NMR (CDCl3, 100.8 MHz): δ = 21.62 (CH3), 21.75 (CH3), 35.18 (CH2), 63.16 (CH), 71.14 (CHCl2), 126.85 (C), 126.94 (CH), 128.40 (CH), 129.65 (CH), 129.70 (CH), 136.07 (C), 141.96 (CH), 144.95 (C), 148.40 (C=O), 155.17 (C=N).

MS: m/z (%) = 439 (1) [M]+, 441 (0.8) [M++2], 242 (34), 244 (21), 197 (45), 159 (100), 155 (63), 132 (38), 115 (30), 91 (95), 89 (31), 65 (53).

Anal. Calcd for C19H19Cl2N3O3S: C, 51.82; H, 4.35; N, 9.54; S, 7.28. Found: C, 52.02; H, 4.42; N, 9.52; S, 7.33.


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5-Dichloromethyl-3-(4-methoxyphenyl)-1-tosylaminocarbonyl-2-pyrazoline (7e)

Yield: 1.10 g (97%); white needles; mp 217 °C (dec) (MeCN).

IR (Nujol): 3314, 1695, 1609, 1346, 1257, 1180, 1069, 832, 788, 733, 665 cm–1.

1H NMR (CDCl3, 400 MHz): δ = 2.43 (s, 3 H), 3.44 (dd, J = 18.2, 11.3 Hz, 1 H), 3.58 (dd, J = 18.2, 5.7 Hz, 1 H), 3.86 (s, 3 H), 4.84 (ddd, J = 11.3, 5.7, 2.6 Hz, 1 H), 6.40 (d, J = 2.6 Hz, 1 H), 6.94 (d, J =8.9 Hz, 2 H), 7.32 (d, J = 8.4 Hz, 2 H), 7.65 (d, J = 8.9 Hz, 2 H), 7.98 (d, J = 8.4 Hz, 2 H), 8.62 (br s, 1 H).

13C NMR (CDCl3, 100.8 MHz): δ = 21.67 (CH3), 35.55 (CH2), 55.80 (CH3), 63.35 (CH), 71.29 (CHCl2), 114.59 (CH), 122.44 (C), 128.49 (CH), 128.73 (CH), 129.64 (CH), 136.55 (C), 144.84 (C), 148.53 (C=O), 154.81 (C=N), 162.37 (C).

MS: m/z (%) = 455 (0.3) [M]+, 457 (0.2) [M++2], 258 (11), 260 (7), 197 (18), 175 (100), 155 (30), 160 (27), 91 (45), 65 (15).

Anal. Calcd for C19H19Cl2N3O4S: C, 50.01; H, 4.20; N, 9.21; S, 7.03. Found: C, 50.04; H, 4.16; N, 9.18; S, 7.07.


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5-Dichloromethyl-3-(4-nitrophenyl)-1-tosylaminocarbonyl-2-pyrazoline (7f)

Yield: 1.10 g (93%); yellow needles; mp 248 °C (dec) (MeCN).

IR (Nujol): 3329, 1709, 1596, 1586, 1517, 1350, 1167, 1087, 1069, 848, 665 cm–1.

1H NMR (DMSO-d 6, 400 MHz): δ = 2.39 (s, 3 H), 3.50 (dd, J = 18.5, 5.5 Hz, 1 H), 3.67 (dd, J = 18.5, 11.5 Hz, 1 H), 5.06 (ddd, J = 11.5, 5.5, 2.8 Hz, 1 H), 6.56 (d, J = 2.8 Hz, 1 H), 7.42 (d, J = 7.9 Hz, 2 H), 7.86 (d, J = 7.9 Hz, 2 H), 8.23 (d, J = 8.6 Hz, 2 H), 8.30 (d, J = 8.6 Hz, 2 H), 11.61 (br s, 1 H).

13C NMR (DMSO-d 6, 100.8 MHz): δ = 21.02 (CH2), 35.14 (CH2), 63.98 (CH), 72.30 (CHCl2), 123.72 (CH), 127.58 (CH), 128.36 (CH), 129.44 (CH), 136.24 (C), 136.86 (C), 144.02 (C), 148.25 (C), 148.96 (C=O), 152.66 (C=N).

MS: m/z (%) = 470 (0.12) [M]+, 398 (6), 334 (25), 273 (4), 197 (22), 190 (61), 155 (61), 144 (34), 91 (100), 65 (32).

Anal. Calcd for C18H16Cl2N4O5S: C, 45.87; H, 3.42; N, 11.89; S, 6.80. Found: C, 45.78; H, 3.40; N, 11.97; S, 6.81.


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5-Dichloromethyl-3-(4-biphenylyl)-1-tosylaminocarbonyl-2-pyrazoline (7g)

Yield: 1.23 g (98%); yellow powder; mp 238 °C (dec) (MeCN/DMF).

IR (Nujol): 3275, 1692, 1594, 1344, 1162, 1076, 896, 841, 788, 732, 702, 663 cm–1.

1H NMR (DMSO-d 6, 400 MHz): δ = 2.39 (s, 3 H), 3.46 (dd, J = 18.4, 5.4 Hz, 1 H), 3.65 (dd, J = 18.4, 11.3 Hz, 1 H), 5.00 (ddd, J = 11.3, 5.4, 2.4 Hz, 1 H), 6.55 (d, J = 2.4 Hz, 1 H), 7.34–7.51 (m, 5 H), 7.68–7.79 (m, 4 H), 7.87 (d, J = 8.2 Hz, 2 H), 8.04 (d, J = 8.3 Hz, 2 H), 11.42 (1 H, br s).

13C NMR (DMSO-d 6, 100.8 MHz): δ = 21.04 (CH3), 34.38 (CH2), 63.43 (CH), 72.46 (CHCl2), 125.58 (C), 126.76 (CH), 127.60 (CH), 127.88 (CH), 128.01 (CH), 129.00 (CH), 129.20 (CH), 129.42 (CH), 137.02 (C), 139.15 (C), 142.09 (C), 143.93 (C), 148.93 (C=O), 154.10 (C=N).

MS: m/z (%) = 501 (1) [M]+, 503 (0.8) [M++2], 429 (9), 304 (24), 306 (16), 221 (100), 197 (12), 155 (19), 91 (36).

Anal. Calcd for C24H21Cl2N3O3S: C, 57.37; H, 4.21; N, 8.36; S, 6.38. Found: C, 57.45; H, 4.22; N, 8.41; S, 6.34.


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5-Dichloromethyl-3-(2-naphthyl)-1-tosylaminocarbonyl-2-pyrazoline (7h)

Yield: 0.99 g (83%); white powder; mp 129–131 °C (dec) (Et2O).

IR (ATR): 3243, 1695, 1597, 1440, 1376, 1067, 756, 780, 659 cm–1.

1H NMR (CDCl3, 400 MHz): δ = 2.49 (s, 3 H), 3.62 (dd, J = 11.4, 18.4 Hz, 1 H), 3.76 (dd, J = 5.7, 18.4 Hz, 1 H), 4.93 (ddd, J = 2.6, 5.7, 11.4 Hz, 1 H), 6.45 (d, J = 2.6 Hz, 1 H), 7.35 (d, J = 8.3 Hz, 2 H), 7.56 (m, 2 H), 7.91 (m, 4 H), 8.03 (d, J = 8.1 Hz, 3 H), 8.75 (s, 1 H).

13C NMR (CDCl3, 100.8 MHz): δ = 22.56 (CH3), 35.95 (CH2), 64.18 (CH), 71.96 (CH), 123.87 (CH), 127.96 (CH), 128.75 (CH), 129.26 (CH), 129.45 (CH), 129.71 (CH), 130.47 (CH), 133.72 (C), 135.40 (C), 136.86 (C), 145.83 (C), 155.92 (C).

HRMS (ESI): m/z [M + H]+ calcd for C22H20Cl2N3O3S: 476.0597; found: 476.0595.


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5-Dichloromethyl-3-(3,4-dichlorophenyl)-1-tosylaminocarbonyl-2-pyrazoline (7i)

Yield: 0.87 g (70%); white powder; mp 205–207 °C (dec) (Et2O).

IR (ATR): 3382, 1741, 1672, 1527, 1446, 1311, 855, 824, 749, 733, 688 cm–1.

1H NMR (DMSO-d 6, 400 MHz): δ = 2.39 (s, 3 H), 3.46 (dd, J = 10.7, 18.2 Hz, 1 H), 3.57 (dd, J = 5.5, 18.2 Hz, 1 H), 4.90 (m, 1 H), 6.39 (d, J = 1.8 Hz, 1 H), 7.35 (d, J = 7.9 Hz, 2 H), 7.54 (q, J = 7.8 Hz, 2 H), 7.80 (s, 1 H), 7.89 (d, J = 8.1 Hz, 2 H), 8.69 (s, 1 H).

13C NMR (DMSO-d 6, 100.8 MHz): δ = 22.41 (CH3), 35.74 (CH2), 64.86 (CH), 73.88 (CH), 126.75 (CH), 129.25 (CH), 129.45 (CH), 130.38 (C), 130.50 (CH), 131.87 (CH), 134.40 (C), 136.40 (C), 136.67 (C), 145.96 (C), 149.05 (C), 153.71 (C).

HRMS (ESI): m/z [M + H]+ calcd for C18H16Cl4N3O3S: 493.9661; found: 493.9679.


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3-(3-Bromophenyl)-5-dichloromethyl-1-tosylaminocarbonyl-2-pyrazoline (7j)

Yield: 1.01 g (80%); white powder; mp 209–210 °C (dec) (Et2O).

IR (ATR): 3240, 1716, 1696, 1442, 1420, 1170, 1072, 767, 664 cm–1.

1H NMR (CDCl3, 400 MHz): δ = 2.43 (s, 3 H), 3.46 (dd, J =11.5, 18.4 Hz, 1 H), 3.57 (dd, J = 5.8, 11.5 Hz, 1 H), 4.89 (ddd, J = 2.6, 5.8, 11.5 Hz, 1 H), 6.40 (d, J = 2.6 Hz, 1 H), 7.3 (m, 3 H), 7.57 (dd, J = 7.7, 0.9 Hz, 1 H), 7.63 (d, J = 7.7 Hz, 1 H), 7.86 (t, J = 1.7 Hz, 1 H), 7.98 (d, J = 8.3 Hz, 2 H), 8.80 (s, 1 H).

13C NMR (CDCl3, 100.8 MHz): δ = 22.60 (CH3), 35.78 (CH2), 64.25 (CH), 71.84 (CH), 123.95, 126.39 (CH), 129.24 (CH), 130.50 (CH), 131.32 (CH), 132.43 (C), 134.96 (CH), 136.70 (C), 145.90 (C), 149.75 (C), 154.49 (C).

HRMS (ESI): m/z [M + H]+ calcd for C18H17BrCl2N3O3S: 503.9546; found: 503.9537.


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Synthesis of 10; General Procedures

Method (a): A suspension of 7 (0.5 mmol) in triethylamine (10 mL) was heated to reflux for 4 h. Then, the solvent was removed in vacuo and the residue was washed with cold water (25 mL), leaving a solid that was collected by filtration, dried and crystallized from the appropriate solvent.

Method (b): Compound 7 (0.5 mmol) and triethylamine (10 mL) were placed in a sealed pressurized reaction vessel and heated at 130 °C for 2 h. After cooling, the solvent was removed in vacuo and the residue was washed with cold water (25 mL), leaving a solid that was collected by filtration, dried and crystallized from the appropriate solvent.

One-Pot Procedure; Method (c): Pyrazoline 5 (0.6 mmol), toluenesulfonyl isocyanate (0.72 mmol) and triethylamine (10 mL) were placed in a sealed pressurized reaction vessel and heated at 130 °C for 2 h. After cooling, the solvent was removed in vacuo and the residue was washed with cold water (25 mL), leaving a solid that was collected by filtration, dried and crystallized from the appropriate solvent.


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2-Phenyl-5-tosyl-4,5-dihydroimidazo[1,5-b]pyrazol-6-one (10a)

Yield: 88 mg (50%) (method A); 134 mg (63%) (method C); white needles; mp 237 °C (dec) (MeOH).

IR (Nujol): 3285, 1698, 1599, 1379, 1346, 1163, 1078, 895, 866, 848, 785, 673 cm–1.

1H NMR (CDCl3, 400 MHz): δ = 2.44 (s, 3 H), 4.92 (s, 2 H), 6.58 (s, 1 H), 7.36–7.42 (m, 5 H), 7.85 (d, J = 6.7 Hz, 2 H), 8.01 (d, J = 7.9 Hz, 2 H).

13C NMR (CDCl3, 100.8 MHz): δ = 21.80 (CH3), 44.53 (CH2), 99.69 (CH), 126.64 (CH), 128.30 (CH), 128.90 (CH), 129.73 (CH), 130.21 (CH), 131.45 (C), 134.46 (C), 140.90 (C), 144.99 (C=O), 146.23 (C), 160.96 (C=N).

MS: m/z (%) = 353 (33) [M]+, 289 (37) [M+– SO2], 260 (14), 245 (10), 199 (9), 155 (19), 128 (100), 115 (29), 91 (98), 65 (34).

Anal. Calcd for C18H15N3O3S: C, 61.18; H, 4.28; N, 11.89; S, 9.07. Found: C, 61.28; H, 4.30; N, 11.95; S, 9.10.


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2-(4-Chlorophenyl)-5-tosyl-4,5-dihydroimidazo[1,5-b]pyrazol-6-one (10b)

Yield: 122 mg (63%) (method b); 174 mg (63%) (method c); white needles; mp 263 °C (dec) (MeOH/CHCl3).

IR (Nujol): 1790, 1598, 1584, 1565, 1434, 1318, 1169, 1110, 818, 731 cm–1.

1H NMR (CDCl3, 400 MHz): δ = 2.45 (s, 3 H), 4.93 (s, 2 H), 6.56 (s, 1 H), 7.39 (br s, 4 H), 7.79 (d, J = 7.1 Hz, 2 H), 8.02 (d, J = 7.3 Hz, 2 H).

13C NMR (CDCl3, 100.8 MHz): δ = 21.83 (CH3), 44.51 (CH2), 99.58 (CH), 127.89 (CH), 128.33 (CH), 129.18 (CH), 129.94 (C), 130.24 (CH), 134.28 (C), 135.75 (C), 141.06 (C), 144.90 (C=O), 146.33 (C), 159.82 (C=N).

MS: m/z (%) = 387 (36) [M]+, 389 (14) [M++ 2], 323 (30) [M+– SO2], 232 (4), 162 (49), 155 (22), 91 (100), 65 (29).

Anal. Calcd for C18H14ClN3O3S: C, 55.74; H, 3.64; N, 10.83; S, 8.27. Found: C, 55.68; H, 3.66; N, 10.78; S, 8.30.


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2-(4-Bromophenyl)-5-tosyl-4,5-dihydroimidazo[1,5-b]pyrazol-6-one (10c)

Yield: 82 mg (38%) (method b); 147 mg (57%) (method c); white powder; mp 260 °C (dec) (MeOH/Me2CO).

IR (Nujol): 1782, 1599, 1320, 1173, 1105, 954, 813, 799, 733, 684 cm–1.

1H NMR (CDCl3, 400 MHz): δ = 2.44 (s, 3 H), 4.91 (d, J =1.0 Hz, 2 H), 6.53 (t, J = 1.0 Hz, 1 H), 7.36 (d, J = 8.2 Hz, 2 H), 7.54 (d, J = 8.5 Hz, 2 H), 7.71 (d, J = 8.5 Hz, 2 H), 8.01 (d, J = 8.2 Hz, 2 H).

13C NMR (CDCl3, 100.8 MHz): δ = 21.75 (CH3), 44.48 (CH2), 99.47 (CH), 124.08 (C), 128.22 (CH), 128.46 (CH), 130.24 (CH), 130.67 (C), 132.21 (CH), 134.73 (C), 141.23 (C), 144.88 (C=O), 146.26 (C), 159.98 (C=N).

MS: m/z (%) = 431 (24) [M]+, 433 (23) [M++ 2], 367 (18) [M+ – SO2], 277 (2), 206 (25), 169 (19), 155 (25), 127 (26), 91 (100), 65 (30).

Anal. Calcd for C18H14BrN3O3S: C, 50.01; H, 3.26; N, 9.72; S, 7.42. Found: C, 50.10; H, 3.30; N, 9.69; S, 7.35.


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2-(p-Tolyl)-5-tosyl-4,5-dihydroimidazo[1,5-b]pyrazol-6-one (10d)

Yield: 121 mg (65%) (method a); 154 mg (70%) (method c); white needles; mp 241 °C (dec) (Me2SO).

IR (Nujol): 1776, 1589, 1330, 1163, 1107, 951, 821, 800, 734, 686, 665 cm–1.

1H NMR (CDCl3, 400 MHz): δ = 2.37 (s, 3 H), 2.43 (s, 3 H), 4.88 (d, J = 1.0 Hz, 2 H), 6.53 (t, J = 1.0 Hz, 1 H), 7.21 (d, J = 8.0 Hz, 2 H), 7.35 (d, J = 8.2 Hz, 2 H), 7.73 (d, J = 8.0 Hz, 2 H), 7.99 (d, J = 8.2 Hz, 2 H).

13C NMR (CDCl3, 100.8 MHz): δ = 21.42 (CH3), 21.77 (CH3), 44.51 (CH2), 99.53 (CH), 126.53 (CH), 128.26 (CH), 128.64 (CH), 129.59 (C), 130.17 (CH), 134.40 (C), 139.87 (C), 140.84 (C), 145.01 (C=O), 146.15 (C), 161.03 (C=N).

MS: m/z (%) = 367 (51) [M]+, 303 (47) [M+ – SO2], 213 (27), 170 (28), 155 (35), 141 (100), 128 (37), 115 (50), 91 (70), 65 (42).

Anal. Calcd for C19H17N3O3S: C, 62.11; H, 4.66; N, 11.44; S, 8.73. Found: C, 62.20; H, 4.69; N, 11.40; S, 8.64.


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2-(4-Methoxyphenyl)-5-tosyl-4,5-dihydroimidazo[1,5-b]pyrazol-6-one (10e)

Yield: 88 mg (46%) (method b); 176 mg (77%) (method c); white needles; mp 185 °C (dec) (MeOH).

IR (Nujol): 1787, 1756, 1616, 1570, 1529, 1332, 1316, 1284, 1251, 1162, 1104, 1034, 817, 731, 668 cm–1.

1H NMR (CDCl3, 300 MHz): δ = 2.42 (s, 3 H), 3.83 (s, 3 H), 4.88 (d, J = 1.2 Hz, 2 H), 6.50 (t, J = 1.2 HZ, 1 H), 6.92 (d, J = 8.8 Hz, 2 H), 7.35 (d, J = 8.3 HZ, 2 H), 7.77 (d, J = 8.8 Hz, 2 H), 7.99 (d, J = 8.3 Hz, 2 H).

13C NMR (CDCl3, 75.4 MHz): δ = 21.77 (CH3), 44.50 (CH2), 55.39 (CH3), 99.30 (CH), 114.25 (CH), 123.98 (C), 128.00 (CH), 128.21 (CH), 130.15 (CH), 134.05 (C), 140.87 (C), 145.02 (C=O), 146.14 (C), 160.75 (C=N).

MS: m/z (%) = 383 (39) [M]+, 319 (7) [M+ – SO2], 228 (12), 172 (27), 158 (100), 143 (28), 115 (39), 91 (65), 65 (22).

Anal. Calcd for C19H17N3O4S: C, 59.52; H, 4.47; N, 10.96; S, 8.36. Found: C, 59.44; H, 4.35; N, 10.91; S, 8.43.


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2-(4-Nitrophenyl)-5-tosyl-4,5-dihydroimidazo[1,5-b]pyrazol-6-one (10f)

Yield: 108 mg (55%) (method b); 211 mg (88%) (method c); white powder; mp 288 °C (dec) (Me2SO).

IR (Nujol): 3121, 1784, 1576, 1517, 1340, 1310, 1164, 1105, 954, 731, 704, 685, 666 cm–1.

1H NMR (DMSO-d 6, 400 MHz): δ = 2.43 (s, 3 H), 5.15 (s, 2 H), 7.04 (s, 1 H), 7.49 (d, J = 8.2 Hz, 2 H), 7.98 (d, J = 8.2 Hz, 2 H), 8.14 (d, J = 8.4 Hz, 2 H), 8.28 (d, J = 8.4 Hz, 2 H).

13C NMR (DMSO-d 6, 100.8 MHz): δ = 20.46 (CH3), 44.60 (CH2), 99.97 (CH), 123.44 (CH), 126.85 (CH), 127.39 (CH), 129.43 (CH), 134.00 (C), 137.23 (C), 142.92 (C), 144.24 (C), 145.20 (C=O), 147.60 (C), 157.13 (C=N).

MS: m/z (%) = 398 (5) [M]+, 334 (23) [M+ – SO2], 243 (3), 173 (7), 155 (26), 114 (9), 91 (100), 65 (30).

Anal. Calcd for C18H14N4O5S: C, 54.27; H, 3.54; N, 14.06; S, 8.05. Found: C, 54.18; H, 3.51; N, 14.16; S, 8.08.


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2-(4-Biphenylyl)-5-tosyl-4,5-dihydroimidazo[1,5-b]pyrazol-6-one (10g)

Yield: 129 mg (60%) (method b); 176 mg (68%) (method c); white powder; mp 276 °C (dec) (MeOH/Me2CO).

IR (Nujol): 1788, 1774, 1594, 1326, 1175, 1106, 950, 801, 769, 727, 669 cm–1.

1H NMR (CDCl3, 400 MHz): δ = 2.45 (s, 3 H), 4.94 (s, 2 H), 6.62 (s, 1 H), 7.35–7.39 (m, 3 H), 7.45 (t, J = 7.5 Hz, 2 H), 7.61 (d, J = 7.5 Hz, 2 H), 7.65 (d, J = 8.2 Hz, 2 H), 7.93 (d, J = 8.2 Hz, 2 H), 8.03 (d, J = 8.3 Hz, 2 H).

13C NMR (CDCl3, 100.8 MHz): δ = 21.75 (CH3), 44.51 (CH2), 99.63 (CH), 127.16 (CH), 127.17 (CH), 127.63 (CH), 127.82 (C), 128.45 (CH), 128.97 (CH), 130.22 (CH), 130.58 (C), 134.78 (C), 140.55 (C), 141.04 (C), 142.67 (C), 144.97 (C=O), 146.19 (C), 160.79 (C=N).

MS: m/z (%) = 429 (71) [M]+, 365 (18) [M+ – SO2], 275 (26), 218 (25), 204 (97), 189 (22), 155 (15), 91 (100), 65 (30).

Anal. Calcd for C24H19N3O3S: C, 67.12; H, 4.46; N, 9.78; S, 7.47. Found: C, 67.03; H, 4.44; N, 9.85; S, 7.50.


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2-(Naphthalen-2-yl)-5-tosyl-4,5-dihydroimidazo[1,5-b]pyrazol-6-one (10h)

Yield: 157 mg (78%) (method a); 198 mg (82%) (method c); white powder; mp 250–251 °C (dec) (Et2O).

IR (ATR): 1722, 1586, 1432, 1374, 1343, 1170, 1105, 780, 686, 661 cm–1.

1H NMR (DMSO-d 6, 400 MHz): δ = 2.40 (s, 3 H), 5.21 (s, 2 H), 7.11 (s, 1 H,), 7.49 (d, J = 8.4 Hz, 2 H), 7.54 (d, J = 8.4 Hz, 2 H), 7.98 (m, 5 H), 8.49 (s, 1 H).

13C NMR (DMSO-d 6, 100.8 MHz): δ = 20.66 (CH3), 44.77 (CH2), 99.53 (CH), 125.32 (CH), 126.21 (CH), 126.38 (CH), 127.22 (CH), 127.53 (CH), 127.90 (CH), 128.10 (CH), 128.62 (CH), 129.59 (C), 132.63 (CH), 133.00 (C), 134.12 (C), 142.68 (C), 144.57 (C), 145.29 (C), 159.47 (C).

HRMS (ESI): m/z [M + H]+ calcd for C22H18N3O3S: 404.1063; found: 404.1051.


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2-(3,4-Dichlorophenyl)-5-tosyl-4,5-dihydroimidazo[1,5-b]pyrazol-6-one (10i)

Yield: 169 mg (80%) (method b); 215 mg (85%) (method c); white powder; mp 252–253 °C (dec) (Et2O).

IR (ATR): 1787, 1595, 1427, 1371, 1346, 1299, 1164, 1105, 1027, 814, 664 cm–1.

1H NMR (DMSO-d 6, 400 MHz): δ = 2.40 (s, 3 H), 5.17 (s, 2 H), 7.08 (s, 1 H), 7.48 (d, J = 4.4 Hz, 2 H), 7.71 (d, J = 6.6 Hz, 1 H), 7.88 (d, J = 6.6 Hz, 1 H), 7.97 (d, J = 4.4 Hz, 2 H), 8.13 (s, 1 H).

13C NMR (DMSO-d 6, 100.8 MHz): δ = 22.48 (CH3), 46.65 (CH2), 101.34 (CH), 127.55 (CH), 129.18 (C), 124.41 (CH), 131.35 (CH), 132.59 (CH), 133.22 (CH), 133.34 (C), 135.43 (C), 144.81 (C), 146.22 (C), 147.15 (C), 158.56 (C).

HRMS (ESI): m/z [M + H]+ calcd for C18H14Cl2N3O3S: 422.0127; found: 422.0146.


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2-(3-Bromophenyl)-5-tosyl-4,5-dihydroimidazo[1,5-b]pyrazol-6-one (10j)

Yield: 143 mg (65%) (method a); 212 mg (82%) (method c); white powder; mp 202–203 °C (dec) (Et2O).

IR (ATR): 1798, 1590, 1364, 1309, 1160, 1170, 782, 727, 686, 661 cm–1.

1H NMR (DMSO-d 6, 400 MHz): δ = 2.41 (s, 3 H), 5.18 (s, 2 H), 7.07 (s, 1 H), 7 (d, J = 8.2 Hz, 2 H), 7.63 (dd, J = 7.0, 14.1 Hz, 2 H), 7.90 (d, J = 7.0 Hz, 1 H), 7.97 (d, J = 8.1 Hz, 2 H), 8.07 (s, 1 H).

13C NMR (DMSO-d 6, 100.8 MHz): δ = 22.49 (CH3), 46.89 (CH2), 101.24 (CH), 123.66 (C), 126.52 (CH), 129.41 (CH), 129.93 (CH), 131.35 (CH), 132.53 (CH), 133.54 (CH), 135.09 (C), 135.45 (C), 144.69 (C), 146.30 (C), 147.13 (C), 159.55 (C).

HRMS (ESI): m/z [M + H]+ calcd for C18H15BrN3O3S: 432.0012; found: 431.9999.


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Synthesis of 11; General Procedure

To a solution of compound 5 (3 mmol) in anhydrous tetrahydrofuran (15 mL), the corresponding isocyanate (3.6 mmol) was added dropwise. The reaction mixture was stirred for 4 h at r.t. under a nitrogen atmosphere. Then, the solvent was evaporated under reduced pressure, obtaining a solid residue that was crystallized from the appropriate solvent. Product 11b was prepared in EtOH instead of THF.


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N-Benzyl-5-dichloromethyl-4,5-dihydro-3-p-tolylpyrazole-1-carboxamide (11a)

Yield: 0.56 g (50%); off-white powder; mp 121–122 °C (dec) (EtOAc/ pet ether).

IR (KBr): 3290, 3207, 6064, 2974, 1946, 1890, 1659, 1571, 1554, 1454, 1366, 1299, 1217, 111, 1080, 1028, 874, 818, 780, 745, 695 cm–1.

1H NMR (CDCl3, 400 MHz): δ = 2.40 (s, 3 H), 3.47 (dd, J = 11.4, 18.2 Hz, 1 H), 3.59 (dd, J = 6.0, 18.2 Hz, 1 H), 4.39 (t, J = 6.0 Hz, 2 H), 4.99 (ddd, J = 2.4, 6, 11.4 Hz, 1 H), 6.43 (t, J = 6 Hz, 1 H), 6.63 (d, J = 2.4 Hz, 1 H), 7.23 (d, J = 8 Hz, 2 H), 7.30 (m, 1 H), 7.37 (m, 4 H), 7.60 (d, J = 8 Hz, 2 H).

13C NMR (CDCl3, 100.8 MHz): δ = 22.39 (CH3), 35.52 (CH2), 44.84 (CH2), 64.55 (CH), 73.46 (CH), 127.33 (CH), 128.26 (CH), 128.46 (CH), 128.79 (C), 129.55 (CH), 130.33 (CH), 139.85 (C), 141.60 (C), 153.09 (C), 155.47 (C).

HRMS (ESI): m/z [M + H]+ calcd for C19H20Cl2N3O: 376.0978; found: 376.0972.


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N-Cyclohexyl-5-dichloromethyl-4,5-dihydro-3-p-tolylpyrazole-1-carboxamide (11b)

Yield: 0.48 g (43%); white powder; mp 158–160 °C (dec) (EtOAc/pet ether).

IR (KBr): 3316, 2931, 2849, 1815, 650, 1595, 1528, 1514, 1449, 1415, 1392, 1326, 1253, 1160, 1134, 1079, 938, 871, 818, 752, 704, 646 cm–1.

1H NMR (CDCl3, 400 MHz): δ = 1.20 (m, 3 H), 1.37 (m, 2 H), 1.63 (d, J = 12 Hz, 1 H), 1.74 (m, 2 H), 1.99 (t, J = 11.6 Hz, 2 H), 2.40 (s, 3 H), 3.45 (dd, J = 11.6, 18 Hz, 1 H), 3.65 (dd, J = 6, 18 Hz, 1 H), 3.68 (m, 1 H), 4.94 (m, 1 H), 5.91 (d, J = 8 Hz, 1 H), 6.55 (d, J = 2 Hz, 1 H), 7.23 (d, J = 8 Hz, 2 H), 7.60 (d, J = 8 Hz, 2 H).

13C NMR (CDCl3, 100.8 MHz): δ = 22.45 (CH3), 25.93 (CH2), 26.47 (CH2), 34.52 (CH2), 34.73 (CH2), 35.48 (CH2), 49.87 (CH), 64.50 (CH), 73.62 (CH), 127.28 (CH), 128.92 (C), 130.30 (CH), 141.46 (C), 152.64 (C), 154.81 (C).

HRMS (ESI): m/z [M + H]+ calcd for C18H24Cl2N3O: 368.1291; found: 368.1297.


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5-Dichloromethyl-N-(2-ethylhexyl)-4,5-dihydro-3-p-tolylpyrazole-1-carboxamide (11c)

Yield: 0.61 g (51%); pale-yellow oil (silica gel column chromatography; pet ether/EtOAc).

IR (KBr): 3604, 3437, 2730, 2019, 1725, 1681, 1528, 1513, 1466, 1376, 1319, 1296, 1251, 1166, 1136, 873, 813, 729, 720, 634 cm–1.

1H NMR (CDCl3, 400 MHz): δ = 0.90 (m, 6 H), 1.32 (m, 9 H), 2.39 (s, 3 H), 3.25 (m, 2 H), 3.44 (dd, J = 11.6, 18.2 Hz, 1 H), 3.55 (dd, J = 6.2, 18.2 Hz, 1 H), 4.94 (ddd, J = 2.6, 6.2, 11.6 Hz, 1 H), 6.03 (d, J = 5.6, 1 H), 6.58 (d, J = 2.6 Hz, 1 H), 7.22 (d, J = 8 Hz, 2 H), 7.59 (d, J = 8 Hz, 2 H).

13C NMR (CDCl3, 100.8 MHz): δ = 11.72 (CH3), 15.04 (CH3), 22.69 (CH3), 23.83 (CH2), 24.98 (CH2), 29.82 (CH2), 31.61 (CH2), 35.68 (CH2), 40.78 (CH), 44.10 (CH2), 64.54 (CH), 73.56 (CH), 127.23 (CH), 128.97 (C), 130.29 (CH), 1141.42 (C), 152.58 (C), 155.64 (C).

HRMS (ESI): m/z [M + H]+ calcd for C20H30Cl2N3O: 398.1760; found: 398.1775.


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5-Dichloromethyl-N-phenyl-4,5-dihydro-3-p-tolylpyrazole-1-carboxamide­ (11d)

Yield: 0.80 g (74%); off-white powder; mp 149–150 °C (dec) (EtOAc/ pet ether).

IR (KBr): 3317, 2989, 1938, 1891, 1665, 1594, 1533, 1501, 1448, 1391, 1329, 1313, 1234, 1144, 1112, 1029, 931, 868, 819, 760, 748, 701, 692, 643 cm–1.

1H NMR (CDCl3, 300 MHz): δ = 2.42 (s, 3 H), 3.57 (dd, J = 11.4, 18 Hz, 1 H), 3.65 (dd, J = 6.1, 18 Hz, 1 H), 5.04 (ddd, J = 2.5, 6.1, 11.4 Hz, 1 H), 6.62 (d, J = 2.5 Hz, 1 H), 7.09 (t, J = 7.6 Hz, 1 H), 7.27 (t, J = 7.6 Hz, 2 H), 7.34 (t, J = 7.6 Hz, 2 H), 7.53 (d, J = 8.6 Hz, 2 H), 7.67 (d, J = 8.6 Hz, 2 H), 8.20 (s, 1 H).

13C NMR (CDCl3, 75.4 MHz): δ = 22.54 (CH3), 35.89 (CH2), 64.44 (CH), 73.26 (CH), 120.30 (CH), 124.41 (CH), 127.58 (CH), 128.66 (C), 130.02 (CH), 130.54 (CH), 139.01 (C), 142.08 (C), 152.68 (C), 153.78 (C).

HRMS (ESI): m/z [M + H]+ calcd for C18H18Cl2N3O: 362.0821; found: 362.0826.


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5-Dichloromethyl-N-p-tolyl-4,5-dihydro-3-p-tolylpyrazole-1-carboxamide­ (11e)

Yield: 0.79 g (70%); off-white powder; mp 155–156 °C (dec) (EtOAc/ pet ether).

IR (KBr): 3387, 2919, 1913, 1667, 1592, 1532, 1416, 1387, 1315, 1233, 1166, 1104, 1028, 933, 868, 812, 758, 748, 734, 698, 646 cm–1.

1H NMR (CDCl3, 400 MHz): δ = 2.33 (s, 3 H), 2.42 (s, 3 H), 3.52 (dd, J = 11.4, 18.4 Hz, 1 H), 3.63 (dd, J = 6, 18.4 Hz, 1 H), 5.03 (ddd, J = 2.2, 6, 11.2 Hz, 1 H), 6.61 (d, J = 2.2 Hz, 1 H), 7.14 (d, J = 8 Hz, 2 H), 7.26 (d, J = 8 Hz, 2 H), 7.40 (d, J = 8 Hz, 2 H), 7.66 (d, J = 8 Hz, 2 H), 7.95 (s, 1 H).

13C NMR (CDCl3, 100.8 MHz): δ = 21.69 (CH3), 22.43 (CH3), 35.75 (CH2), 64.33 (CH), 73.20 (CH), 120.37 (CH), 127.45 (CH), 128.57 (C), 130.41 (CH), 133.89 (C), 136.24 (C), 141.92 (C), 152.71 (C), 153.56 (C).

HRMS (ESI): m/z [M + H]+ calcd for C19H20Cl2N3O: 376.0978; found: 376.0980.


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5-Dichloromethyl-N-(4-chlorophenyl)-4,5-dihydro-3-p-tolylpyrazole-1-carboxamide (11f)

Yield: 0.83 g (70%); white needles; mp 174–175 °C (dec) (EtOAc/pet ether).

IR (KBr): 3396, 3066, 1907, 1669, 1590, 1525, 1494, 1416, 1310, 1230, 1166, 1136, 1090, 1010, 935, 846, 757, 729, 673 cm–1.

1H NMR (CDCl3, 400 MHz): δ = 2.43 (s, 3 H), 3.54 (dd, J = 11.6, 18.4 Hz, 1 H), 3.65 (dd, J = 5.6, 18.4 Hz, 1 H), 5.04 (m, 1 H), 6.60 (br s, 1 H), 7.29 (m, 4 H), 7.48 (d, J = 8.4 Hz, 4 H), 7.66 (d, J = 7.6 Hz, 2 H), 8.02 (s, 1 H).

13C NMR (CDCl3, 100.8 MHz): δ = 22.45 (CH3), 35.84 (CH2), 64.27 (CH), 72.99 (CH), 121.33 (CH), 127.50 (CH), 128.38 (C), 129.18 (C), 129.88 (CH), 130.46 (CH), 137.52 (C), 142.13 (C), 152.36 (C), 153.99 (C).

HRMS (ESI): m/z [M + H]+ calcd for C18H17Cl3N3O: 396.0432; found: 396.0434.


#

5-Dichloromethyl-N-(4-fluorophenyl)-4,5-dihydro-3-p-tolylpyrazole-1-carboxamide (11g)

Yield: 0.82 g (72%); off-white needles; mp 165 °C (dec) (Me2CHOH).

IR (KBr): 3384, 3295, 3029, 1882, 1667, 1636, 1610, 1593, 1510, 1418, 13866, 1525, 1313, 1210, 1096, 849, 832, 767, 734, 703, 607 cm–1.

1H NMR (CDCl3, 300 MHz): δ = 2.42 (s, 3 H), 3.54 (dd, J = 11.4, 18.1 Hz, 1 H), 3.64 (dd, J = 6.3, 18.1 Hz, 1 H), 5.03 (m, 1 H), 6.59 (d, J = 1.8 Hz, 1 H), 7.03 (t, J = 8.4 Hz, 2 H), 7.27 (d, J = 6.6 Hz, 2 H), 7.47 (dd, J = 4.5, 8.7 Hz, 2 H), 7.66 (d, J = 7.8 Hz, 2 H), 7.96 (s, 1 H).

13C NMR (CDCl3, 75.4 MHz): δ = 22.54 (CH3), 35.92 (CH2), 64.42 (CH), 73.17 (CH), 116.62 (d, J = 22.4 Hz, CH), 122.13 (d, J = 7.8 Hz, CH), 127.57 (CH), 128.57 (C), 130.55 (CH), 134.92 (d, J = 2.3 Hz, C), 142.16 (C), 152.77 (C), 153.94 (C).

HRMS (ESI): m/z [M + H]+ calcd for C18H17Cl2FN3O: 380.0727; found: 380.0735.


#

N-(4-Bromophenyl)-5-(dichloromethyl)-4,5-dihydro-3-p-tolylpyrazole-1-carboxamide (11h)

Yield: 0.94 g (71%); white needles; mp 189–191 °C (dec) (EtOAc/pet ether).

IR (KBr): 3398, 1894, 1673, 1587, 1526, 1513, 1488, 1406, 1324, 1312, 1231, 1071, 1008, 843, 814, 805, 756, 729, 655 cm–1.

1H NMR (CDCl3, 300 MHz): δ = 2.42 (s, 3 H), 3.54 (dd, J = 11.2, 18.3 Hz, 1 H), 3.65 (dd, J = 6.3, 18.3 Hz, 1 H), 5.02 (ddd, J = 2.6, 6.3, 11.2 Hz, 1 H), 6.58 (d, J = 2.6 Hz, 1 H), 7.27 (d, J = 8.0 Hz, 2 H), 7.43 (m, 4 H), 7.66 (d, J = 8.0 Hz, 2 H), 8.00 (s, 1 H).

13C NMR (CDCl3, 75.4 MHz): δ = 22.55 (CH3), 35.95 (CH2), 64.36 (CH), 73.07 (CH), 116.82 (C), 121.75 (CH), 127.61 (CH), 128.48 (C), 130.56 (CH), 132.93 (CH), 138.15 (C), 142.25 (C), 152.41 (C), 154.12 (C).

HRMS (ESI): m/z [M + H]+ calcd for C18H17BrCl2N3O: 439.9927; found: 439.9942.


#

5-Dichloromethyl-4,5-dihydro-N-p-tolyl-3-phenylpyrazole-1-carboxamide (11i)

Yield: 0.69 g (63%); white needles; mp 196 °C (dec) (EtOAc/pet ether).

IR (KBr): 3307, 1659, 1593, 1539, 1442, 1403, 1250, 1172, 933, 783, 764, 738, 689 cm–1.

1H NMR (CDCl3, 300 MHz): δ = 2.34 (s, 3 H), 3.52 (dd, J = 11.3, 18.4 Hz, 1 H), 3.64 (dd, J = 6.3, 18.4 Hz, 1 H), 5.03 (ddd, J = 2.4, 6.3, 11.3 Hz, 1 H), 6.12 (d, J = 2.4 Hz, 2 H), 6.89 (d, J = 7.4 Hz, 1 H), 7.20 (t, J = 7.8 Hz, 2 H), 7.28 (d, J = 8.1 Hz, 1 H), 7.37 (s, 1 H), 7.45 (m, 3 H), 7.76 (dd, J = 3.4, 6.8 Hz, 2 H), 7.95 (s, 1 H).

13C NMR (CDCl3, 75.4 MHz): δ = 22.52 (CH3), 35.81 (CH2), 64.57 (CH2), 73.20 (CH), 117.38 (CH), 120.93 (CH), 125.29 (CH), 127.60 (CH), 129.82 (CH), 131.45 (C), 131.61 (CH), 138.85 (C), 139.94 (C), 152.66 (C), 153.61 (C).

HRMS (ESI): m/z [M + H]+ calcd for C18H18Cl2N3O: 362.0821; found: 362.0821.


#

5-Dichloromethyl-4,5-dihydro-3-(naphthalen-3-yl)-N-phenylpyrazole-1-carboxamide (11j)

Yield: 0.73 g (61%); off-white powder; mp 146–146 °C (dec) (EtOAc/ pet ether).

IR (KBr): 3382, 1741, 1672, 1595, 1527, 1466, 1323, 825, 749, 688 cm–1.

1H NMR (CDCl3, 300 MHz): δ = 3.65 (dd, J = 11.2, 18.1 Hz, 1 H), 3.78 (dd, J = 6.0, 18.1 Hz, 1 H), 5.09 (ddd, J = 2.4, 6.0, 11.2 Hz, 1 H), 7.08 (t, J = 7.4 Hz, 1 H), 7.34 (t, J = 8.1 Hz, 2 H), 7.54 (m, 4 H), 7.88 (m, 3 H), 8.02 (t, J = 7.4 Hz, 3 H).

13C NMR (CDCl3, 75.4 MHz): δ = 35.80 (CH2), 64.80 (CH), 73.31 (CH), 120.36 (CH), 124.01 (CH), 124.51 (CH), 127.94 (CH), 128.34 (CH), 128.49 (CH), 128.82 (CH), 128.97 (C), 129.48 (CH), 129.62 (CH), 130.04 (CH), 133.98 (C), 135.24 (C), 138.94 (C), 152.59 (C), 153.70 (C).

HRMS (ESI): m/z [M + H]+ calcd for C21H18Cl2N3O: 398.0821; found: 398.0834.


#

3-(3-Bromophenyl)-5-dichloromethyl-4,5-dihydro-N-phenylpyrazole-1-carboxamide (11k)

Yield: 0.77 g (61%); off-white powder; mp 138–140 °C (dec) (EtOAc/ pet ether).

IR (KBr): 3308, 1597, 1663, 1530, 1446, 1315, 1233, 873, 764, 750, 688 cm–1.

1H NMR (CDCl3, 400 MHz): δ = 3.59 (dd, J = 11.3, 18.1 Hz, 1 H), 3.64 (dd, J = 5.9, 18.1 Hz, 1 H), 5.01 (m, 1 H), 6.62 (d, J = 1.8 Hz, 2 H), 7.10 (t, J = 7.4 Hz, 1 H), 7.35 (t, J = 7.6 Hz, 2 H), 7.59 (d, J = 6.9 Hz, 1 H), 7.37 (d, J = 7.6 Hz, 1 H), 7.95 (d, J = 9.8 Hz, 2 H).

13C NMR (CDCl3, 100.8 MHz): δ = 35.56 (CH2), 64.60 (CH), 72.92 (CH), 120.31 (CH), 123.95 (C), 124.52 (CH), 126.05 (CH), 129.64 (CH), 130.29 (CH), 131.24 (CH), 133.39 (C), 134.33 (CH), 138.63 (C), 152.16 (C), 152.36 (C).

HRMS (ESI): m/z [M + H]+ calcd for C17H15BrCl2N3O: 425.977; found: 425.980.


#

Synthesis of 12; General Procedure

A mixture of 11 (3 mmol), dioxane (5 mL), and DBU (9 mmol) was stirred for 3 h at 100 °C. The solvent was then evaporated under reduced pressure, leaving a solid residue that was crystallized from the appropriate solvent.


#

5-Benzyl-2-p-tolyl-4,5-dihydroimidazo[1,5-b]pyrazol-6-one (12a)

Yield: 0.36 g (40%); white powder; mp 202–203 °C (dec) (Me2CHOH/H2O).

IR (KBr): 3476, 3031, 1948, 1746, 1585, 1495, 1467, 1445, 1406, 1314, 1298, 1246, 1077, 986, 930, 826, 806, 746, 699, 657, 623 cm–1.

1H NMR (CDCl3, 400 MHz): δ = 2.37 (s, 3 H), 4.24 (br s, 2 H), 4.69 (br s, 2 H), 7.22 (d, J = 6.8 Hz, 2 H), 7.33 (m, 5 H), 7.79 (d, J = 6.8 Hz, 2 H).

13C NMR (CDCl3, 100.8 MHz): δ = 22.20 (CH3), 44.16 (CH2), 48.78 (CH2), 99.08 (CH), 127.12 (CH), 129.12 (CH), 129.91 (CH), 130.27 (CH), 130.43 (C), 136.40 (C), 139.76 (C), 142.66 (C), 150.76 (C), 159.69 (C).

HRMS (ESI): m/z [M + H]+ calcd for C19H18N3O: 304.1444; found: 304.1443.


#

5-Cyclohexyl-2-p-tolyl-4,5-dihydroimidazo[1,5-b]pyrazol-6-one (12b)

Yield: 0.62 g (70%); beige powder; mp 201–203 °C (dec) (Me2CHOH/H2O).

IR (KBr): 3326, 2930, 2851, 1753, 1626, 1575, 1445, 1317, 1298, 1229, 1088, 892, 804, 741, 641 cm–1.

1H NMR (DMSO-d 6, 400 MHz): δ = 1.50 (t, J = 9.2 Hz, 2 H), 1.63 (m, 2 H), 1.76 (d, J = 9.6 Hz, 2 H), 1.79 (s, 1 H), 2.32 (s, 3 H), 3.77 (s, 1 H), 4.52 (s, 2 H), 5.56 (d, J = 7.2 Hz, 1 H), 6.83 (s, 1 H), 7.24 (d, J = 7.6 Hz, 2 H), 7.77 (d, J = 7.6 Hz, 2 H).

13C NMR (DMSO-d 6, 100.8 MHz): δ = 22.19 (CH3), 25.78 (CH2), 26.31 (CH2), 26.66 (CH2), 31.43 (CH2), 34.67 (CH2), 48.83 (CH2), 53.54 (CH), 99.23 (CH), 127.09 (CH), 130.71 (CH), 131.08 (C), 139.48 (C), 144.76 (C), 149.91 (C), 158.49 (C).

HRMS (ESI): m/z [M + H]+ calcd for C18H22N3O: 296.1757; found: 296.1757.


#

5-(2-Ethylhexyl)-2-p-tolyl-4,5-dihydroimidazo[1,5-b]pyrazol-6-one (12c)

Yield: 0.52 g (53%); off-white powder; mp 106–107 °C (dec) (Me2CHOH/H2O).

IR (KBr): 3399, 2960, 2927, 1748, 1674, 1633, 1586, 1529, 1466, 1445, 1406, 1315, 1297, 1236, 1117, 1100, 108, 804, 739, 665 cm–1.

1H NMR (CDCl3, 400 MHz): δ = 1.25 (m, 13 H), 2.38 (s, 3 H), 3.09 (d, J = 4 Hz, 2 H), 3.43 (t, J = 6.8 Hz, 2 H), 4.38 (s, 2 H), 6.52 (s, 1 H), 7.24 (d, J = 8 Hz, 2 H), 7.79 (d, J = 8 Hz, 2 H).

13C NMR (CDCl3, 100.8 MHz): δ = 11.33 (CH3), 11.76 (CH3), 14.96 (CH3), 22.22 (CH), 23.91 (CH2), 24.48 (CH2), 25.00 (CH2), 29.44 (CH2), 29.78 (CH2), 31.23 (CH2), 31.81 (CH2), 38.88 (CH), 40.61 (CH), 44.33 (CH2), 45.20 (CH2), 48.61 (CH2), 98.92 (CH), 127.09 (CH), 130.28 (CH), 130.43 (C), 139.73 (C), 142.53 (C), 151.04 (C), 159.50 (C).

HRMS (ESI): m/z [M + H]+ calcd for C20H28N3O: 326.2227; found: 326.2235.


#

5-Phenyl-2-p-tolyl-4,5-dihydroimidazo[1,5-b]pyrazol-6-one (12d)

Yield: 0.61 g (70%); white powder; mp 260–261 °C (dec) (Me2CHOH/H2O).

IR (KBr): 3063, 1932, 1742, 1599, 1591, 1505, 1459, 1443, 1386, 1324, 1298, 1274, 1173, 1113, 1082, 1065, 953, 856, 836, 812, 745, 686, 656 cm–1.

1H NMR (DMSO-d 6, 300 MHz): δ = 2.32 (s, 3 H), 5.09 (s, 2 H), 6.94 (s, 1 H), 7.19 (m, 1 H), 7.20 (d, J = 9.8 Hz, 2 H), 7.44 (t, J = 9.8 Hz, 2 H), 7.73 (d, J = 10.6 Hz, 2 H), 7.81 (d, J = 10.6 Hz, 2 H).

13C NMR (DMSO-d 6, 75.4 MHz): δ = 22.35 (CH3), 46.19 (CH2), 99.65 (CH), 120.44 (CH), 125.95 (CH), 127.36 (CH), 130.59 (C), 130.91 (CH), 139.95 (C), 143.86 (C), 148.77 (C), 159.44 (C).

HRMS (ESI): m/z [M + H]+ calcd for C18H16N3O: 290.1288; found: 290.1293.


#

2,5-Di-p-tolyl-4,5-dihydroimidazo[1,5-b]pyrazol-6-one (12e)

Yield: 0.68 g (75%); off-white powder; mp 230–231 °C (dec) (Me2CHOH/H2O).

IR (KBr): 3304, 2916, 1894, 1748, 1640, 1594, 1564, 1516, 1442, 1384, 1325, 1297, 1239, 1168, 1065, 953, 860, 813, 731, 627 cm–1.

1H NMR (DMF-d 7, 400 MHz, 100 °C): δ = 2.37 (s, 3 H), 2.97 (3 H, s), 5.11 (s, 2 H), 6.84 (s, 1 H), 7.29 (d, J = 2.0 Hz, 2 H), 7.31 (d, J = 2.0 Hz, 2 H), 7.55 (d, J = 8.2 Hz, 2 H), 7.87 (d, J = 8.2 Hz, 2 H).

13C NMR (DMF-d 7, 100.8 MHz, 100 °C): δ = 20.82 (CH3), 21.30 (CH3), 45.98 (CH2), 98.94 (CH), 120.67 (CH), 127.08 (CH), 130.29 (CH), 130.49 (C), 131.21 (CH), 135.34 (C), 137.47 (C), 139.60 (C), 143.50 (C), 148.65 (C), 159.63 (C).

HRMS (ESI): m/z [M + H]+ calcd for C19H18N3O: 304.1444; found: 304.1453.


#

5-(4-Chlorophenyl)-2-p-tolyl-4,5-dihydroimidazo[1,5-b]pyrazol-6-one (12f)

Yield: 0.81 g (83%); white needles; mp 298–299 °C (dec) (Me2NCHO).

IR (KBr): 3296, 1914, 1744, 1633, 1590, 1561, 1496, 1443, 1394, 1328, 1299, 1288, 1098, 954, 859, 823, 801, 732, 629 cm–1.

1H NMR (DMF-d 7, 400 MHz, 110 °C): δ = 2.52 (s, 3 H), 5.27 (s, 2 H), 6.96 (s, 1 H), 7.42 (d, J = 7.6 Hz, 2 H), 7.63 (d, J = 8.8 Hz, 2 H), 7.97 (d, J = 8.8 Hz, 2 H), 7.98 (d, J = 7.6 Hz, 2 H).

13C NMR (DMF-d 7, 100.8 MHz): δ = 21.35 (CH3), 46.07 (CH2), 99.39 (CH), 122.15 (CH), 127.25 (CH), 130.06 (CH), 130.38 (CH), 131.30 (C), 139.11 (C), 139.86 (C), 143.59 (C), 148.78 (C), 160.14 (C).

HRMS (ESI): m/z [M + H]+ calcd for C18H15ClN3O: 324.0898; found: 324.0892.


#

5-(4-Fluorophenyl)-2-p-tolyl-4,5-dihydroimidazo[1,5-b]pyrazol-6-one (12g)

Yield: 0.57 g (62%); white needles; mp 300 °C (dec) (Me2NCHO).

IR (KBr): 3150, 2926, 1870, 1743, 1581, 1564, 1512, 1442, 1398, 1327, 1299, 1230, 1174, 1116, 1066, 954, 865, 823, 797, 732, 610 cm–1.

1H NMR (DMF-d 7, 400 MHz, 110 °C): δ = 2.38 (m, 3 H), 5.12 (s, 2 H), 6.82 (s, 1 H), 7.26 (m, 4 H), 7.88 (m, 4 H).

13C NMR (DMF-d 7, 100.8 MHz): δ = 26.48 (CH3), 51.50 (CH2), 104.26 (CH), 121.80 (d, J = 22.9 Hz, CH), 128.2 (d, J = 8.1 Hz, CH), 132.34 (CH), 135.50 (CH), 136.43 (C), 141.54 (C), 144.89 (C), 148.75 (C), 154.01 (C), 164.79 (C), 165.07 (C).

HRMS (ESI): m/z [M + H]+ calcd for C18H15FN3O: 308.1194; found: 308.1196.


#

5-(4-Bromophenyl)-2-p-tolyl-4,5-dihydroimidazo[1,5-b]pyrazol-6-one (12h)

Yield: 0.71 g (64%); white needles; mp 306–307 °C (dec) (Me2NCHO).

IR (KBr): 3297, 1892, 11744, 1634, 1589, 1558, 1488, 1443, 1391, 1327, 1299, 1284, 1237, 1173, 1070, 1064, 1005, 954, 857, 823, 800, 732, 629 cm–1.

1H NMR (CDCl3+TFA-d 1, 400 MHz): δ = 2.52 (s, 3 H), 5.12 (s, 2 H), 7.52 (d, J = 4 Hz, 1 H), 7.52 (m, 4 H), 7.71 (d, J = 8.2 Hz, 2 H), 7.84 (d, J = 8.2 Hz, 2 H).

13C NMR (CDCl3+TFA-d 1, 100.8 MHz): δ = 22.57 (CH3), 49.88 (CH2), 103.38 (C), 124.71 (C), 125.12 (CH), 129.71 (CH), 133.26 (CH), 135.64 (CH), 136.29 (C), 147.37 (C), 148.88 (C), 149.67 (C), 160.41 (C).

HRMS (ESI): m/z [M + H]+ calcd for C18H15BrN3O: 368.0393; found: 368.0404.


#

5-p-Tolyl-2-phenyl-4,5-dihydroimidazo[1,5-b]pyrazol-6-one (12i)

Yield: 0.44 g (51%); white powder; mp 130–133 °C (dec) (Me2CHOH/H2O).

IR (KBr): 3467, 1735, 1589, 1495, 1440, 1389, 1328, 1199, 083, 955, 776, 733, 697 cm–1.

1H NMR (CDCl3+TFA-d 1, 400 MHz): δ = 2.38 (s, 3 H), 4.97 (s, 2 H), 6.72 (s, 1 H), 7.27 (s, 2 H), 7.55 (m, 4 H), 7.76 (m, 2 H).

13C NMR (CDCl3+TFA-d 1, 100.8 MHz): δ = 21.73 (CH3), 46.94 (CH2), 100.67 (CH), 121.61 (CH), 127.64 (CH), 130.05 (CH), 131.11 (CH), 134.88 (C), 137.77 (C), 142.65 (C), 148.77 (C), 160.75 (C).

HRMS (ESI): m/z [M + H]+ calcd for C18H16N3O: 290.1288; found: 290.1294.


#

2-(Naphthalen-3-yl)-5-phenyl-4,5-dihydroimidazo[1,5-b]pyrazol-6-one (12j)

Yield: 0.53 g (54%); white powder; mp 170–172 °C (dec) (CHCl3/pet ether).

IR (ATR): 2961, 1740, 1583, 1501, 1436, 1385, 1366, 1293, 1171, 970, 862, 794, 681 cm–1.

1H NMR (DMF-d 7, 400 MHz): δ = 5.23 (s, 2 H), 7.11 (s, 1 H), 7.27 (t, J = 7.1 Hz, 2 H), 7.51 (t, J = 7.7 Hz, 2 H), 7.57 (m, 2 H), 7.86 (d, J = 8.3 Hz, 2 H), 7.98 (d, J = 7.0 Hz, 1 H), 8.00 (s, 2 H), 8.17 (d, J = 8.6 Hz, 1 H), 8.54 (s, 1 H).

13C NMR (DMF-d 7, 100.8 MHz): δ = 45.95 (CH2), 99.48 (CH), 120.40 (CH), 124.94 (CH), 125.60 (CH), 126.31 (CH), 127.43 (CH), 128.65 (CH), 129.25 (CH), 129.36 (CH), 130.05 (CH), 131.32 (C), 134.59 (C), 134.65 (C), 139.97 (C), 143.74 (C), 148.62 (C), 159.58 (C).

HRMS (ESI): m/z [M + H]+ calcd for C21H16N3O: 326.1288; found: 326.1278.


#

2-(3-Bromophenyl)-5-phenyl-4,5-dihydroimidazo[1,5-b]pyrazol-6-one (12k)

Yield: 0.53 g (50%); white needles; mp 132–133 °C (dec) (EtOH).

IR (ATR): 3064, 1714, 1598, 1502, 1391, 1311, 1203, 1065, 785, 751, 679 cm–1.

1H NMR (DMSO-d 6, 400 MHz): δ = 5.13 (s, 2 H), 7.08 (s, 1 H), 7.22 (t, J = 6.4 Hz, 1 H), 7.45 (q, J = 8.5 Hz, 3 H), 7.61 (d, J = 7.9 Hz, 1 H), 7.76 (d, J = 7.8 Hz, 2 H), 7.97 (d, J = 7.3 Hz, 1 H), 8.13 (s, 1 H).

13C NMR (DMSO-d 6, 100.8 MHz): δ = 46.21 (CH2), 100.06 (CH), 119.40 (C), 120.49 (CH), 123.64 (C), 126.00 (CH), 126.29 (CH), 129.73 (CH), 129.96 (C), 130.49 (CH), 132.46 (CH), 132.99 (CH), 139.67 (C), 144.02 (C), 148.50 (C), 157.68 (C).

HRMS (ESI): m/z [M + H]+ calcd for C17H13BrN3O: 354.0237; found: 354.0244.


#
#

Supporting Information

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  • 35 Vicentini CB, Veronese AC, Manfrini M, Guarneri M. Tetrahedron 1996; 52: 7179
  • 36 Vicentini CB, Manfrini M, Mazzanti M, Scatturin A, Romagnoli C, Mares D. Arch. Pharm. (Weinheim, Ger.) 1999; 332: 337
  • 37 Beck JP, Gilligan PJ. WO 9910350A1, 1999
  • 38 Romagnoli C, Mares D, Bruni A, Andreotti E, Manfrini M, Vicentini CB. Mycopathologia 2002; 153: 129
  • 39 Elgemeie GH, Elghandour AH, Ali HA, Hussein AM. Synth. Commun. 2002; 32: 2245
  • 40 Popil’nichenko SV, Brovarets BS, Drach BS. Russ. J. Org. Chem. 2004; 40: 219
  • 41 Liubchak K, Tolmachev A, Nazarenko K. J. Org. Chem. 2012; 77: 3365
  • 42 El-Borai MA, Rizk HF, Sadek MR, El-Keiy MM. Green Sustainable Chem. 2016; 6: 88
  • 43 Lantos I, Oh H, Razgaitis C, Loev B. J. Org. Chem. 1978; 43: 4841
  • 44 Michels JG, Wright GC. J. Org. Chem. 1969; 34: 3213
  • 45 Gnichtel H, Belkien L, Totz W, Wawretschek L. Liebigs Ann. Chem. 1980; 1016
  • 46 Schweizer EE, Lee KJ. J. Org. Chem. 1984; 49: 4848
  • 47 Schweizer EE, Lee KJ. J. Org. Chem. 1984; 49: 1964
  • 48 Rheingold AL, Fultz WC, Schweizer EE, Lee KJ. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1984; 40: 687
  • 49 Blass BE, Srivastava A, Coburn KR, Faulkner AL, Janusz JJ, Ridgeway JM, Seibel WL. Tetrahedron Lett. 2004; 45: 619
  • 50 Blass BE, Srivastava A, Coburn KR, Faulkner AL, Janusz JJ, Ridgeway JM, Seibel WL. Tetrahedron Lett. 2004; 45: 1275
  • 51 Atta SM. S. Bull. Natl. Res. Cent. (Egypt) 1994; 19: 91
  • 52 Vicentini CB, Veronese AC, Manfrini M. J. Heterocycl. Chem. 1997; 34: 629
  • 53 Luknitskii FI. Chem. Rev. 1975; 75: 259
  • 54 Guirado A, Martiz B, Andreu R, Bautista D. Tetrahedron 2009; 65: 5958
  • 55 Guirado A, Martiz B, Andreu R, Galvez J. Electrochim. Acta 2008; 53: 7138
  • 56 Shaabani A, Nazeri Mohammad T, Afshari R. Mol. Diversity 2018; 22: 207
  • 57 Guirado A, Martiz B, Andreu R, Bautista D, Galvez J. Tetrahedron 2007; 63: 1175
  • 58 CCDC 1899508 (10d) contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
  • 59 CCDC 1899509 (11f) contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
  • 60 CCDC 1899510 (12h) contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.

Corresponding Author

Antonio Guirado
Departamento de Química Orgánica, Facultad de Química, Universidad de Murcia
Campus de Espinardo, 30071 Murcia
Spain

Publication History

Received: 13 July 2020

Accepted after revision: 27 August 2020

Publication Date:
07 October 2020 (online)

© 2020. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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  • 35 Vicentini CB, Veronese AC, Manfrini M, Guarneri M. Tetrahedron 1996; 52: 7179
  • 36 Vicentini CB, Manfrini M, Mazzanti M, Scatturin A, Romagnoli C, Mares D. Arch. Pharm. (Weinheim, Ger.) 1999; 332: 337
  • 37 Beck JP, Gilligan PJ. WO 9910350A1, 1999
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  • 39 Elgemeie GH, Elghandour AH, Ali HA, Hussein AM. Synth. Commun. 2002; 32: 2245
  • 40 Popil’nichenko SV, Brovarets BS, Drach BS. Russ. J. Org. Chem. 2004; 40: 219
  • 41 Liubchak K, Tolmachev A, Nazarenko K. J. Org. Chem. 2012; 77: 3365
  • 42 El-Borai MA, Rizk HF, Sadek MR, El-Keiy MM. Green Sustainable Chem. 2016; 6: 88
  • 43 Lantos I, Oh H, Razgaitis C, Loev B. J. Org. Chem. 1978; 43: 4841
  • 44 Michels JG, Wright GC. J. Org. Chem. 1969; 34: 3213
  • 45 Gnichtel H, Belkien L, Totz W, Wawretschek L. Liebigs Ann. Chem. 1980; 1016
  • 46 Schweizer EE, Lee KJ. J. Org. Chem. 1984; 49: 4848
  • 47 Schweizer EE, Lee KJ. J. Org. Chem. 1984; 49: 1964
  • 48 Rheingold AL, Fultz WC, Schweizer EE, Lee KJ. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1984; 40: 687
  • 49 Blass BE, Srivastava A, Coburn KR, Faulkner AL, Janusz JJ, Ridgeway JM, Seibel WL. Tetrahedron Lett. 2004; 45: 619
  • 50 Blass BE, Srivastava A, Coburn KR, Faulkner AL, Janusz JJ, Ridgeway JM, Seibel WL. Tetrahedron Lett. 2004; 45: 1275
  • 51 Atta SM. S. Bull. Natl. Res. Cent. (Egypt) 1994; 19: 91
  • 52 Vicentini CB, Veronese AC, Manfrini M. J. Heterocycl. Chem. 1997; 34: 629
  • 53 Luknitskii FI. Chem. Rev. 1975; 75: 259
  • 54 Guirado A, Martiz B, Andreu R, Bautista D. Tetrahedron 2009; 65: 5958
  • 55 Guirado A, Martiz B, Andreu R, Galvez J. Electrochim. Acta 2008; 53: 7138
  • 56 Shaabani A, Nazeri Mohammad T, Afshari R. Mol. Diversity 2018; 22: 207
  • 57 Guirado A, Martiz B, Andreu R, Bautista D, Galvez J. Tetrahedron 2007; 63: 1175
  • 58 CCDC 1899508 (10d) contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
  • 59 CCDC 1899509 (11f) contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
  • 60 CCDC 1899510 (12h) contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.

Zoom Image
Scheme 1 Synthesis of 5-dichloromethyl-2-pyrazolines 5 through chloral derivatives. Ar: (a) C6H5; (b) 4-ClC6H4; (c) 4-BrC6H4; (d) 4-MeC6H4; (e) 4-MeOC6H4; (f) 4-O2NC6H4; (g) 4-PhC6H4; (h) 2-C10H7; (i) 2,4-Cl2C6H3; (j) 3-BrC6H4
Zoom Image
Figure 1 X-ray crystal structure of compound 10d (thermal ellipsoids drawn at the 50% probability level)
Zoom Image
Scheme 2 Synthesis of 2-aryl-5-tosyl-4,5-dihydroimidazo[1,5-b]pyrazol-6-ones 10 from pyrazolines 5
Zoom Image
Figure 2 X-ray crystal structure of compound 11f (thermal ellipsoids drawn at the 50% probability level)
Zoom Image
Figure 3 X-ray crystal structure of compound 12h (thermal ellipsoids drawn at the 50% probability level)