Ethoxymethylene Malononitrile Synthesis Essay

DOI: 10.1039/C4RA05346J (Paper) RSC Adv., 2014, 4, 35629-35634

One-pot NHC-assisted access to 2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-ones†

Received 5th June 2014 , Accepted 31st July 2014

First published on 1st August 2014


An efficient N-heterocyclic carbene-assisted one-pot reaction for the synthesis of 2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-ones from 2-(ethoxymethylene)malononitrile, guanidines (or amidines) and ketones (or aldehydes) has been developed. This highly efficient method includes a series of conversions such as Michael addition, cyclisation, isomerization, aromatization, then nucleophilic attack and Dimroth rearrangement. And it avoids complicated reagents and multiple steps.


Introduction

Pyrimidine and fused cyclic compounds are widely present in many natural and biologically active compounds.1 As a subtype, pyrimidopyrimidinones possess a wide range of biological activities such as anti-inflammatory,1 antitumor,2 inhibition of dihydrofolate reductase,3 type-II kinase inhibition,4 tyrosine kinase inhibition,5 and as a surrogate for both T and A in duplex DNA.6 The traditional approaches relay on multiple steps reactions,6a,7 such as the condensation of aldehyde and acid anhydride with 4-aminopyrimidine-5-carboxamides, which are always hydrolyzed from the corresponding o-aminonitriles,8 or with the 5-aminopyrimidine-4-carbonitriles,9 the cyclization of ethyl 5-aminopyrimidine-4-carboxylates with acrylamides,10 the treatment of 6-aminouracil/6-amino-5,6-dihydropyrimidin-4(3H)-one with phosphorus oxychloride in DMF under the Vilsmeier reaction conditions.3,6 However, they usually suffer from drawbacks such as multistep sequences,11 complicated reagents,12 longer reaction time and lower yields.3,13

One-pot reaction improves the efficiency of reaction. It saves time and resources, and avoids the lengthy separation and purification process of intermediate compounds.14N-hetero-cyclic carbenes (NHCs) as the small organic molecular catalysts have been used widely as powerful tool for the construction of complex compounds.15 NHCs can catalyze the Benzoin condensation,16 Stetter reaction,17 transesterification/acylation reactions,19c,18 nucleophilic substitution reaction,19 and domino reaction.20 In our previous studies, NHC-PPIm was easily prepared via concentration of a 1,3-dipropylimidazolium hydroxide aqueous solution and excellent catalytic activity was found in the cyclocondensation of cyclohexanone and 2-aminobenzonitrile.21 Inspired by this good result, especially taking into account both the synthesis of dihydropyrimidinone through PDF conversion22 and the synthesis of 4-amino-5-cyanopyrimidine in the catalyst of base,23 we designed a novel one-pot NHC-PPIm assisted three component heterocyclization of 2-(ethoxymethylene)malononitrile, guanidines and ketones for the synthesis of dihydropyrimido[4,5-d]pyrimidin-4(1H)-one (Scheme 1). To the best of our knowledge, this is a first convenient method for the construction of pyrimido[4,5-d]pyrimidin-4(1H)-one core by NHC-PPIm assisted three components cyclization, and this one-pot approach is mild, inexpensive, energy efficient and avoids transition metal catalyst.


Scheme 1 The retrosynthetic design of reaction.

Results and discussion

To find the appropriate reaction conditions, we chose the reaction of 2-(ethoxymethylene)malononitrile (1.2 mmol), guanidine (1 mmol) and cyclohexanone as the model. Different reaction conditions were evaluated, and the results were summarized in Table 1. It is shown that inorganic bases and organic weak bases didn't promote this reaction (Table 1, entries 1–4). However, organic strong base could promote it easily (Table 1, entries 5–7). NHC-PPIm could promote this reaction under mild conditions, and the yield is higher in ethanol (Table 1, entries 8–11). Although higher temperature improved the reaction, NHC-PPIm was unstable at this case, so the appropriate temperature was 40 °C (Table 1, entries 12–14). The amount of NHC-PPIm has a little effect on the reaction when it is more than 0.4 equivalent. So 0.4 equivalent amount of NHC-PPIm was an appropriate choice (Table 1, entries 15–18).

Table 1Optimization of reaction conditionsa



With the optimal conditions in hand, a series of ketones (or benzaldehyde) and guanidines (or amidines) were investigated, and the results were summarized in Table 2. Theoretically, different carbonyl compounds had effect on this reaction because of the steric hindrance and ring tension, but all carbonyl compounds reacted with guanidine were in good yields (Table 2, entries 1–9), and partially the N,N-dimethylguanidine also gave the corresponding compounds in good yields (Table 2, entries 10–14). To expand the scope of this one-pot reaction methodology, a set of guanidines and amidines were selected and the corresponding compounds were obtained in good to excellent yields (Table 2, entries 15–19). These results illustrated the universality of NHC-PPIm and the advantages of one-pot method.

Table 2NHC-PPIm-assisted three-component one-pot synthesis of 2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-onesa



To rationalize the above results, a possible reaction mechanism is envisioned as depicted in Scheme 2. It is proposed that the 2-(ethoxymethylene)malononitrile undergoes a Michael addition reaction with guanidines (or amidines), then followed by cyclisation, isomerization and aromatization to afford intermediate 4-aminopyrimidine-5-carbonitrile 5. The Breslow intermediate 6 nucleophilic attacks the cyano of the 5 to provide 7. Then 7 releases NHC-PPIm and 3,1-oxazine 8 is formed, which subsequently rearranges to afford the final product 4 (Dimroth rearrangement24).


Scheme 2 The possible mechanism of the formation of 4.

In order to prove this mechanism, we tried to seperate the intermediate 5j, and fortunately, 4-amino-2-dimethylamino-pyrimidine-5-carbonitrile (5j) was detected by LC after 10 minutes. As the reaction proceeded, the final product 4j increased and the intermediate 5j decreased (Fig. 1). The product 4j was also obtained by the condensation of the seperated intermediate 5j with cyclohexanone in the same conditions in 83% yield.


Fig. 1 Percentage of intermediate and product: (●)5j, (▼)4j.

All products were characterized by IR, 1H NMR, 13C NMR, ESI spectra, and elemental analysis. And the structure 4b was undoubtedly confirmed by X-ray crystallographic analysis (Fig. 2).25


Fig. 2 ORTEP representation of 4b.

Conclusions

In summary, an efficient method for combining two fairly well-known reactions into one-pot reaction and synthesizing 2,3-dihydropyrimido[4,5-d]pyrimidin4(1H)-ones was developed. It is a highly efficient method for synthesizing pyrimido[4,5-d]pyrimidine ring without starting from any nitrogen-containing heterocyclic compound. The reaction conducted under mild conditions and the most products deposited from the solvent when the reaction completed.

Experimental section

General methods

The starting materials including 2-(ethoxymethylene)malononitrile (1), guanidines/amidines (2) and ketones (3) are commercially available. Melting points were determined using XT4 microscope melting point apparatus (uncorrected). Infrared (IR) spectra were recorded on a Perkin Elmer FT-IR spectrophotometer with KBr pellets. 1H and 13C NMR spectra were recorded at a Bruker 400 or 500 MHz spectrometer with TMS as the internal standard. Mass spectra were recorded on a ZAB-HS mass spectrometer using ESI ionization. Elemental analyses were performed on an Elementar Vario EL. The percentage of intermediate and product were determined by HPLC using an Shimadzu LC-20AT instrument with Hanbon column YWG C18.

General procedure for the synthesis of 4

2-(Ethoxymethylene)malononitrile (1, 1.2 mmol) and guanidine/amidine (2, 1 mmol) were mixed in ethanol at room temperature, then ketone (3, 1.2 mmol) and NHC-PPIm (0.4 mmol) was added. The mixture was warmed to 40 °C. At the end of the reaction (TLC monitoring), the reaction mixture was cooled to room temperature. The solid was filtered and recrystallized from methanol or purified by column chromatography on silica gel (200–300 mesh silica gels) to afford pure 4a.

4-Amino-2-(dimethylamino)pyrimidine-5-carbonitrile (5j). White solid; m.p. 217–219 °C; IR (KBr, v, cm−1): 3424, 3390, 3336, 3203, 2215, 1661, 1602, 1555, 1529, 1487; 1H NMR (400 MHz, CDCl3) (δ, ppm): 8.22 (s, 1H), 5.17 (s, 2H), 3.19 (s, 3H), 3.14 (s, 3H); 13C NMR (100 MHz, CDCl3) (δ, ppm): 162.6, 161.6, 161.4, 117.6, 77.7, 36.4; ESI-MS (m/z) = 164 ([M + H]+).

7′-Amino-1'H-spiro[cyclohexane-1,2′-pyrimido[4,5-d]pyrimidin]-4′(3′H)-one (4a). White solid; m.p. > 300 °C; IR (KBr, v, cm−1): 3315, 3180, 2935, 2851, 1662, 1609, 1472, 1446, 1421; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.18 (s, 1H), 7.79 (s, 1H), 7.73 (s, 1H), 6.64 (s, 2H), 1.66–1.64 (m, 5H), 1.60–1.55 (m, 5H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 164.7, 162.2, 161.1, 156.7, 97.6, 67.7, 38.1, 24.5, 20.7; ESI-MS (m/z) = 232 ([M − H]). Anal. calcd for C11H15N5O: C, 56.64; H, 6.48; N, 30.02%. Found: C, 56.44; H, 6.58; N, 30.07%.

7′-Amino-1′'H-spiro[cycloheptane-1,2′-pyrimido[4,5-d]pyrimidin]-4′(3′H)-one (4b). Light yellow solid; m.p. > 300 °C; IR (KBr, v, cm−1): 3413, 3339, 3173, 2933, 2845, 1659, 1624, 1600, 1473, 1408; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.17 (s, 1H), 7.89 (s, 1H), 7.88 (s,1H), 6.61 (s, 2H), 1.87–1.84 (m, 4H), 1.4 (s, 8H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 164.7, 162.0, 161.0, 156.7, 97.4, 71.8, 42.0, 29.4, 20.7; ESI-MS (m/z) = 248 ([M + H]+); Anal. calcd for C12H17N5O:C, 58.28; H, 6.93; N, 28.32%. Found: C, 58.14; H, 6.76; N, 28.62%.
7-Amino-2,2-dimethyl-2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-one (4c). Yellow solid; m.p. > 300 °C; IR (KBr, v, cm−1): 3464, 3229, 3148, 2943, 1663, 1615, 1482, 1455, 1418; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.18 (s, 1H), 7.77 (s, 1H), 7.75 (s, 1H), 6.68 (s, 2H), 1.37 (s, 6H);13C NMR (100 MHz, DMSO-d6) (δ, ppm): 164.9, 162.0, 161.0, 156.8, 97.2, 66.7, 29.9; ESI-MS (m/z) = 216 ([M + Na]+); Anal. calcd. for C8H11N5O:C, 49.73; H, 5.74; N, 36.25%. Found: C, 49.55; H, 5.70; N, 36.36%.
7-Amino-2-ethyl-2-methyl-2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-one (4d). Yellow solid; m.p. > 300 °C; IR (KBr, v, cm−1): 3228, 2969, 1648, 1611, 1447; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.14 (s, 1H), 7.67 (s, 2H), 6.60 (s, 2H), 1.62–1.59 (m, 2H), 1.33 (s, 3H), 0.81 (t, J = 6.8 Hz 3H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 164.7, 162.0, 161.3, 156.4, 96.9, 69.2, 34.6, 29.0, 7.9; ESI-MS (m/z) = 206 ([M − H]); Anal. calcd for C9H13N5O:C, 52.16; H, 6.32; N, 33.79%. Found: C, 52.22; H, 6.52; N, 33.66%.
7-Amino-2-methyl-2-propyl-2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-one (4e). White solid; m.p. > 300 °C; IR (KBr, v, cm−1): 3336, 3225, 3142, 2962, 1678, 1608, 1574, 1474, 1415; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.13 (s, 1H), 7.69 (s, 2H), 6.62 (s, 2H), 1.60–1.55 (m, 2H), 1.33 (s, 3H), 1.28 (t, J = 8 Hz, 2H), 0.83 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 164.7, 162.0, 161.0, 156.4, 97.0, 68.9, 44.5, 29.2, 16.4, 13.9; ESI-MS (m/z) = 220 ([M − H]); Anal. calcd for C10H15N5O:C, 54.28; H, 6.83; N, 31.65%. Found: C, 54.38; H, 6.78; N, 31.58%.
7-Amino-2,2-diethyl-2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-one (4f). White solid; m.p. > 300 °C; IR (KBr, v, cm−1): 3156, 2970, 2936, 1671, 1600, 1477, 1419; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.11 (s, 1H), 7.54 (s, 1H), 7.49 (s,1H), 6.54 (s, 2H), 1.60–1.53 (m, 4H), 0.81 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 164.7, 162.3, 161.5, 156.1, 96.5, 79.2, 72.1, 34.2, 7.5; ESI-MS (m/z) = 244 ([M + Na]+); Anal. calcd for C10H15N5O:C, 54.28; H, 6.83; N, 31.65%. Found: C, 54.55; H, 6.72; N, 31.59%.
7-Amino-2-isopropyl-2-methyl-2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-one (4g). White solid; m.p. > 300 °C; IR (KBr, v, cm−1): 3416, 3173, 2970, 1657, 1605, 1566, 1482, 1414; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.12 (s, 1H), 7.75 (s, 1H), 7.72 (s,1H), 6.58 (s, 2H), 1.77–1.86 (m, 1H), 1.32 (s, 3H), 0.85 (d, J = 1.6 Hz, 3H), 0.83 (d, J = 2.0 Hz, 3H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 164.7, 161.8, 161.0, 156.2, 97.1, 71.3, 38.9, 25.9, 16.6; ESI-MS (m/z) = 244 ([M + Na]+); Anal. calcd for C10H15N5O:C, 54.28; H, 6.83; N, 31.65%. Found: C, 54.42; H, 6.93; N, 31.50%.
7-Amino-2-methyl-2-phenyl-2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-one (4h). Yellow solid; m.p. > 300 °C; IR (KBr, v, cm−1): 3453, 3329, 1665, 1577, 1444; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.58 (s, 1H), 8.52 (s, 1H), 8.12 (s,1H), 7.45 (d, J = 7.6 Hz, 2H), 7.33 (t, J = 7.2 Hz, 2H), 7.22 (t, J = 7.8 Hz, 1H), 6.72 (s, 2H), 1.65 (s, 3H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 164.6, 163.0, 161.8, 157.2, 147.6, 128.2, 127.4, 124.7, 98.2, 69.6, 30.1; ESI-MS (m/z) = 254 ([M − H]); Anal. calcd for C13H13N5O:C, 61.17; H, 5.13; N, 27.43%. Found: C, 61.34; H, 5.33; N, 27.16%.
7-Amino-2-phenyl-2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-one (4i). White solid; m.p. > 300 °C; IR (KBr, v, cm−1): 3464, 3299, 3090, 2938, 1673, 1643, 1606, 1565, 1475, 1420; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.21 (s, 1H), 8.20 (s, 1H), 8.16 (s, 1H), 7.39–7.38 (m, 4H), 7.33 (q, J = 4.4 Hz, 1H), 6.78 (s, 2H), 5.73 (s, 1H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 164.7, 162.2, 161.5, 156.9, 142.5, 128.4, 128.3, 126.0, 98.0, 64.9; ESI-MS (m/z) = 264 ([M + Na]+); Anal. calcd for C12H11N5O:C, 59.74; H, 4.60; N, 29.03%. Found: C, 59.62; H, 4.33; N, 29.23%.
7′-(Dimethylamino)-1′H-spiro[cyclohexane-1,2′-pyrimido[4,5-d]pyrimidin]-4′(3′H)-one (4j). White solid; m.p. > 300 °C; IR (KBr, v, cm−1): 3170, 3055, 2930, 2860, 1647, 1606, 1547, 1503, 1448; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.25 (s, 1H), 7.85 (s, 1H), 7.80 (s, 1H), 3.00 (s, 6H), 1.68–1.57 (m, 8H), 1.34–1.25 (m, 2H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 163.6, 163.1, 161.4, 156.7, 97.5, 66.6, 38.7, 37.4, 25.3, 21.3; ESI-MS (m/z) = 262 ([M + H]+); Anal. calcd for C13H19N5O:C, 59.75; H, 7.33; N, 26.80%. Found: C, 59.81; H, 7.30; N, 26.68%.
7-(Dimethylamino)-2,2-dimethyl-2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-one (4k). Light yellow solid; m.p. > 300 °C; IR (KBr, v, cm−1): 3251, 3139, 2973, 1737, 1633, 1607, 1575, 1440; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.27 (s, 1H), 7.90 (s, 1H), 7.84 (s, 1H), 3.10 (s, 6H), 1.39 (s, 6H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 162.9, 162.1, 160.5, 156.1, 96.4, 66.7, 36.6, 29.8; ESI-MS (m/z) = 222 ([M + H]+); Anal. calcd for C10H15N5O:C, 54.28; H, 6.83; N, 31.65%. Found: C, 54.41; H, 6.81; N, 31.58%.
7-(Dimethylamino)-2-ethyl-2-methyl-2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-one (4l). White solid; m.p. 257–259 °C; IR (KBr, v, cm−1): 3207, 2979, 2924, 1635, 1608, 1583, 1542, 1517, 1459; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.26 (s, 1H), 7.78 (s, 1H), 7.72 (s, 1H), 3.10 (s, 6H), 1.67–1.62 (m, 2H), 1.36 (s, 3H), 0.83 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 162.9, 162.3, 160.7, 155.8, 96.1, 69.3, 36.6, 34.9, 29.2, 7.9; ESI-MS (m/z) = 236 ([M + H]+); Anal. calcd for C11H17N5O:C, 56.15; H, 7.28; N, 29.77%. Found: C, 55.99; H, 7.32; N, 29.81%.
7-(Dimethylamino)-2-methyl-2-propyl-2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-one (4m). White solid; m.p. 252–254 °C; IR (KBr, v, cm−1): 3202, 2958, 2934, 2873, 1638, 1608, 1583, 1542, 1519, 1459; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.24 (s, 1H), 7.79 (s, 1H), 7.72 (s, 1H), 3.10 (s, 6H), 1.63–1.57 (m, 2H), 1.35 (s, 3H), 1.32–1.28 (m, 2H), 0.84 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 162.9, 162.1, 160.6, 155.7, 96.1, 69.0, 44.6, 36.6, 29.4, 16.5, 13.9; ESI-MS (m/z) = 250 ([M + H]+); Anal. calcd for C12H19N5O:C, 57.81; H, 7.68; N, 28.09%. Found: C, 57.75; H, 7.72; N, 28.21%.
7-(Dimethylamino)-2-isopropyl-2-methyl-2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-one (4n). Light yellow solid; m.p. 279–281 °C; IR (KBr, v, cm−1): 3242, 3180, 2967, 2935, 1641, 1606, 1577, 1541, 1515, 1449, 1389; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.23 (s, 1H), 7.83 (s, 1H), 7.75 (s, 1H), 3.10 (s, 6H), 1.89–1.82 (m, 1H), 1.35 (s, 3H), 0.86 (d, J = 6 Hz, 6H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 162.9, 162.0, 160.5, 155.6, 96.3, 71.5, 36.6, 26.1, 16.6; ESI-MS (m/z) = 250 ([M + H]+); Anal. calcd for C12H19N5O:C, 57.81; H, 7.68; N, 28.09%. Found: C, 57.61; H, 7.75; N, 28.18%.
7′-(Phenylamino)-1′H-spiro[cyclohexane-1,2′-pyrimido[4,5-d]pyrimidin]-4′(3′H)-one (4o). White solid; m.p. 292–294 °C; IR (KBr, v, cm−1): 3200, 2923, 1647, 1594, 1574, 1531, 1498, 1443; 1H NMR (500 MHz, DMSO-d6) (δ, ppm): 9.53 (s, 1H), 8.35 (s, 1H), 8.02 (s, 1H), 7.99(s, 1H), 7.81 (d, J = 7.5 Hz, 2H), 7.28 (t, J = 7.5 Hz, 2H), 6.97 (t, J = 8.5 Hz, 1H), 1.75–1.61 (m, 8H), 1.39–1.29 (m, 2H); 13C NMR (500 MHz, DMSO-d6) (δ, ppm): 162.5, 161.9, 161.2, 156.7, 140.7, 128.9, 122.1, 120.0, 99.2, 66.6, 38.6, 24.9, 21.0; ESI-MS (m/z) = 310 ([M + H]+); Anal. calcd for C17H19N5O:C,66.00; H, 6.19; N, 22.64%. Found: C, 66.11; H, 6.17; N, 22.58%.
7′-(Methylamino)-1′H-spiro[cycloheptane-1,2′-pyrimido[4,5-d]pyrimidin]-4′(3′H)-one (4p). Yellow solid; m.p. > 300 °C; IR (KBr, v, cm−1): 3253, 2929, 1655, 1595, 1530, 1461, 1380; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.17 (s, 1H), 8.00 (s, 1H), 7.84 (s, 1H), 7.18 (s, 1H), 2.78 (s, 3H), 1.88–1.82 (m, 4H), 1.50 (s, 8H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 164.6, 162.6, 161.2, 156.7, 96.9, 72.3, 31.2, 30.0, 28.5, 21.3; ESI-MS (m/z) = 262 ([M + H]+); Anal. calcd for C13H19N5O:C, 59.75; H, 7.33; N, 26.80%. Found: C, 59.88; H, 7.31; N, 26.74%.
7′-(Ethylamino)-1′H-spiro[cyclohexane-1,2′-pyrimido[4,5-d]pyrimidin]-4′(3′H)-one (4q). White solid; m.p. > 300 °C; IR (KBr, v, cm−1): 3195, 2935, 1633, 1587, 1517, 1454, 1432, 1389; 1H NMR (500 MHz, DMSO-d6) (δ, ppm): 8.18 (s, 1H), 7.81 (s, 1H), 7.76 (s, 1H), 7.26 (s, 1H), 3.26 (m, 2H), 1.67–1.58 (m, 8H), 1.36–1.24 (m, 2H), 1.09 (t, J = 5.4 Hz, 3H); 13C NMR (500 MHz, DMSO-d6) (δ, ppm): 164.0, 162.3, 161.3, 157.0, 97.2, 68.0, 38.6, 35.8, 25.1, 21.1, 15.3; ESI-MS (m/z) = 262 ([M + H]+); Anal. calcd for C13H19N5O:C, 59.75; H, 7.33; N, 26.80%. Found: C, 59.68; H, 7.32; N, 26.84%.
2,2-Dimethyl-7-phenyl-2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-one (4r). White solid; m.p. 282–284 °C; IR (KBr, v, cm−1): 3234, 3061, 2960, 1674, 1611, 1592, 1448, 1440; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.65 (s, 1H), 8.61 (s, 1H), 8.34 (s, 1H), 8.32 (d, J = 2 Hz, 2H), 7.52–7.50 (m, 3H), 1.48 (s, 6H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 166.9, 160.9, 160.3, 154.9, 137.1, 131.1, 128.5, 128.0, 104.2, 67.2, 30.1; ESI-MS (m/z) = 255 ([M + H]+); Anal. calcd for C14H14N4O:C, 66.13; H, 5.55; N, 22.03%. Found: C, 66.27; H, 5.53; N, 21.98%.
2,2,7-Trimethyl-2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-one (4s). White solid; m.p. > 300 °C; IR (KBr, v, cm−1): 3190, 3050, 2923, 1684, 1613, 1555, 1424; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.43 (s, 1H), 8.42 (s, 1H), 8.27 (s, 1H), 2.37 (s, 3H), 1.41 (s, 6H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 170.6, 161.0, 159.9, 154.4, 103.3, 67.0, 30.0, 25.8; ESI-MS (m/z) = 193 ([M + H]+); Anal. calcd for C9H12N4O:C, 56.24; H, 6.29; N, 29.15%. Found: C, 56.12; H, 6.31; N, 29.21%.

Acknowledgements

This work was supported by the grant of Beijing Institute of Technology. We are grateful for analytical help of Institute of Chemistry, Chinese Academy of Sciences and Beijing Normal University.

Notes and references

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  25. ESI.†.

Footnote

† Electronic supplementary information (ESI) available. CCDC 896461. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra05346j

This journal is © The Royal Society of Chemistry 2014

EntrySolventNHC-PPIm (eqiv.)Time (h)Temp (°C)Yieldb (%)
1EtOHNaOH (1.0)7RefluxTrace
2EtOHNa2CO3 (1.0)7Reflux0
3EtOHDBU (1.0)7Reflux0
4EtOHpyridine (1.0)7Reflux0
5EtOHNaOMe (1.0)7Reflux79
6EtOHNaOEt (1.0)7Reflux80
7EtOHKOBu-t (1.0)7Reflux70
8EtOHNHC-PPIm (1.0)22575
9PhMeNHC-PPIm (1.0)22560
10(CH2)5CONHC-PPIm (1.0)22572
11H2ONHC-PPIm (1.0)24072
12EtOHNHC-PPIm (1.0)24084
13EtOHNHC-PPIm (1.0)26070
14EtOHNHC-PPIm (1.0)28049
15EtOHNHC-PPIm (0)2400
16EtOHNHC-PPIm (0.2)24042
17EtOHNHC-PPIm (0.4)24085
18EtOHNHC-PPIm (0.8)24084

1Chemical Industries Division, National Research Centre, Dokki, Giza 12622, Egypt

2Chemistry Department, Faculty of Science, Jazan University, Saudi Arabia

3Applied Organic Chemistry Department, National Research Centre, Dokki, Giza 12622, Egypt

4Chemistry Department, Faculty of Science, Shaqra University, Al Dawadmi, Saudi Arabia

5Chemical Engineering Department, King Saud University, P.O. Box 800, Riyadh 11421, Saudi Arabia

Copyright © 2014 Rizk E. Khidre et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The current review summarizes the known synthetic routes of fused imidazopyrazoles. This review is classified into two main categories based on the type of annulations, for example, annulation of the imidazole ring onto a pyrazole scaffold or annulation of the pyrazole ring onto an imidazole scaffold. Some medicinal applications of imidazopyrazoles are mentioned.

1. Introduction

Over the past two decades, imidazopyrazole and related drugs have been attracting the attention of the medicinal chemists due to their considerable biological and pharmacological activities. Medicinal properties of imidazopyrazole derivatives include anticancer [1–11]; for example, 2,3-dihydro-1H-imidazo[1,2-b]pyrazoles have in vivo effects on the proliferation of mouse leukemic [1], and the same compound has antiviral activity in herpes simplex virus type 1-infected mammalian cells [12], and substituted imidazo[1,2-b]pyrazole (cephem derivatives) is used as antimicrobials [13–15]. Also, imidazo[1,2-b]pyrazole nucleus used as photographic dye-forming couplers comprise, useful in photographic materials and processes, have improved absorption [16–19]. In view of the above fact and in connection to our previous review articles about biologically active heterocyclic systems [20–25], we decided to prepare this review to present for the reader a survey of the literature of the different azoles linked directly with imidazole nucleus; also some of the medicinal applications are mentioned.

Fused imidazopyrazole refers to three isomers according to the conjunction between imidazole and pyrazole nucleus. The three isomers of imidazopyrazole are shown in Figure 1.

Figure 1

Today, there are several approaches available for the synthesis of imidazopyrazoles and they may be classified into two main categories:(a)annulation of the imidazole ring onto a pyrazole scaffold;(b)annulation of the pyrazole ring onto an imidazole scaffold.

2. Synthesis by Annulation of the Imidazole Ring onto a Pyrazole Scaffold

2.1. Synthesis of Imidazo[1,2-b]Pyrazole

Ethyl 5-amino-1-(2-hydroxy-2-phenylethyl)-1H-pyrazole-4-carboxylate 3, obtained by reaction of 2-hydrazino-1-phenylethanol 1 with ethyl (ethoxymethylene)cyanoacetate 2, was treated with concentrated sulphuric acid at 0°C to give the 2-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carboxylate 4. Also, on condensation of 1 with ethoxymethylenemalononitrile in absolute ethanol the 5-amino-1-(2-hydroxy-2-phenylethyl)-1H-pyrazole-4-carbonitrile 6 was obtained and then hydrolysed in alkaline ethanol/water solution to form 5-amino-1-(2-hydroxy-2-phenylethyl)-1H-pyrazole-4-carboxamide 7. Finally, 2-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carboxamide 8 was prepared by cyclization in the presence of concentrated sulphuric acid [26]. The synthesized 2-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole derivatives were tested in vitro in order to evaluate their ability to interfere with human neutrophil functions. All tested compounds showed strong inhibition of fMLP-OMe-induced chemotaxis (Scheme 1) [26, 27].

Scheme 1

The synthesis of imidazo[1,2-b]pyrazoles was reported; thus the condensation of the hydrazinoacetaldehyde synthon with electrophiles such as ethyl (ethoxymethylene)cyanoacetate 2 and 3-oxo-2-phenylpropanenitrile 9 gave ethyl 5-amino-1-(2,2-diethoxyethyl)-1H-pyrazole-4-carboxylate 10 and 1-(2,2-diethoxyethyl)-4-phenyl-1H-pyrazol-5-amine 12, respectively. The latter compounds were cyclized in acid to produce imidazopyrazoles 11 and 13, respectively. Similarly, ethyl 5-amino-1-(2,2-diethoxyethyl)-1H-pyrazole-4-carboxylate 14 was reacted with hydrazine followed by reaction with nitrous acid to afford 1H-imidazo[1,2-b]pyrazole-7-carbonyl azide 15 rearranged to produce carbamates 16 [28] (Scheme 2).

Scheme 2

A series of 1H-imidazo[1,2-b]pyrazolecarboxylate derivatives were synthesized from reaction between ethyl cyanopyruvate sodium 17 and hydrazinoacetaldehyde diethylacetal in a biphasic water/chloroform in the presence of sulfuric acid to give ethyl 5-amino-1-(2,2-diethoxyethyl)-1H-pyrazole-3-carboxylate 18 followed by cyclization to give imidazopyrazole 19. The synthesized compounds were evaluated in vitro for 5-HT3 receptor affinity. The biochemical data show significant activity for these derivatives (Scheme 3) [29]. On the other hand, imidazo[1,2-b]pyrazole-7-carbonitrile was prepared by the condensation of 2-hydrazinoacetaldehyde diethyl acetal with (ethoxymethylene)malononitrile 5, which gave pyrazole followed by ring closure under acid-catalyzed hydrolytic conditions to afford imidazopyrazole 21 [30] (Scheme 3).

Scheme 3

Amino-l-(2-hydroxyethyl)pyrazole 22 was formylated, treated with methanesulfonyl chloride and triethylamine, and then followed by cyclization with sodium hydride, to give 1-formyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole 23 [31] (Scheme 4).

Scheme 4

3-Amino-5-phenylpyrazoles 25 were reacted with 2-(4-methyl-2-phenyl-1,3-thiazol-5-yl)-2-oxo-N-phenylethanehydrazonoyl bromide 24 in boiling ethanol to give 3-phenylazo-2-(4-methyl-2-phenyl-thiazol-5-yl)-6-phenyl-5H-imidazo[1,2-b]pyrazoles 26 (Scheme 5) [32].

Scheme 5

In the same fashion, it was reported that equimolar amounts of hydrazonoyl bromides 27 and 32 were reacted with 5-amino-3-phenyl-1H-pyrazole 25 in ethanol under reflux to afford the corresponding imidazo[1,2-b]pyrazoles 31 and 34, respectively (Scheme 6) [33, 34].

Scheme 6

5-Aminopyrazole 25 was reacted with hydrazonyl halides such as 2-oxo--arylpropanehydrazonoyl chlorides 35 [35–37] and 2-bromobenzofurylglyoxal-2-arylhydrazones 37 [38] in ethanol at reflux temperature to give 6-phenyl-3-(aryldiazenyl)-5H-imidazo[1,2-b]pyrazoles 36 and 38, respectively (Scheme 7).

Scheme 7

Regioselective cyclization reaction between compound 25 and oxaldiimidoyl dichlorides 39 in THF in the presence of triethylamine afforded 3H-imidazo[1,2-b]pyrazoles 40 in good yields [39] (Scheme 8).

Scheme 8

Appel’s dehydration conditions of (2-oxo-1,2-diphenylethylidene)hydrazono)-N-phenylbutanamide 41, prepared from reaction of benzil hydrazone with acetoacetanilide, led to azinoketimine 42 which underwent electrocyclic ring closure under the reaction conditions to give imidazo[1,2-b]pyrazole-2-one 49 and 1H-imidazo[1,2-b]pyrazole 50 [40] (Scheme 9).

Scheme 9

In the same fashion, treatment of N-aziridinylimino carboxamides 52 prepared by the reaction of 1-amino-2-phenylaziridine 51 with acetoacetanilide in tetrahydrofuran at room temperature with a mixture of triphenylphosphine, carbon tetrachloride, and triethylamine (Appel’s condition) in dichloromethane at reflux temperature led to the formation of 2,3-dihydro-1H-imidazo[1,2-b]-pyrazoles 56 (54–82%) as a major product [41] (Scheme 10).

Scheme 10

5-Amino-3-phenyl-1H-pyrazole 25 was reacted with hydroximoyl chloride 57 in ethanol at room temperature to give 3-nitroso-2-aryl-6-phenyl-1H-imidazo[1,2-b]pyrazoles 58 in 60–75% yields [30] (Scheme 11).

Scheme 11

Intermolecular aza-Wittig reaction of 5-(triphenylphosphoranylideneamino)-3-phenylpyrazole 60 with -chloroketone, namely, 2-chloro-2-phenylacetophenone, chloroacetylchloride, and 1-chloro-1-(phenyldiazenyl)propan-2-one, afforded the imidazo[1,2-b]pyrazole derivatives 62ac via elimination of hydrogen chloride from the initially formed intermediate 61 [42] (Scheme 12).

Scheme 12

A series of 2-aryl-7-cyano/ethoxycarbonyl-6-methylthio-1H-imidazo[1,2-b]pyrazoles 65 have been synthesized in moderate to good yields, via reaction of 5-amino-4-cyano/ethoxycarbonyl-3-methylthio-1H-pyrazole 63 with either -bromoacetophenones or -tosyloxyacetophenones followed by cyclocondensation of the formed intermediate 64 under acidic conditions. Using -tosyloxyacetophenones instead of -bromoacetophenones in the previous reaction has such advantages that the reactions gave the final products in higher yields, became more eco-friendly as well as less time consuming, and avoided highly lachrymatory and toxc -haloketones which are now not available commercially. Fungicidal activity of the synthesized compound was studied [43, 44] (Scheme 13).

Scheme 13

3-Antipyrinyl-5-aminopyrazole 66 was reacted with either ethyl -chloroacetoacetate or chloroacetyl chloride to yield 1-(2-hydroxy-3H-imidazo[1,2-b]pyrazol-3-yl)ethanone 67 and 3H-imidazo[1,2-b]pyrazol-2-ol 68, respectively [45] (Scheme 14).

Scheme 14

7-Chloro-6-methyl-2-phenyl-3-(phenylsulfinyl)-1H-imidazo[1,2-b]pyrazole 69, useful as starting materials for color photograph couplers and dyes, was prepared from treating 5-amino-4-chloro-3-methyl-1H-pyrazole 68 with phenacyl bromide in the presence of -collidine, reacting the product with PhSSPh in the presence of NaH and heating at 60° in the presence of HCl [46] (Scheme 15).

Scheme 15

Ethyl 2-hydrazinylacetate hydrochloride 70 was reacted with 2-oxo-,2-diphenylacetohydrazonoyl cyanide 71 to afford 6-phenyl-7-(phenyldiazenyl)-1H-imidazo[1,2-b]pyrazole-2(3H)-one 72 [47] (Scheme 16).

Scheme 16

1H-Imidazo[1,2-b]pyrazole-7-carbonitrile derivatives, which are spleen tyrosine kinase (syk) inhibitors, are useful in the treatment of syk-mediated diseases. Thus, substituted imidazo[1,2-b]pyrazole-7-carbonitrile 76 was prepared by cyclocondensation of aminopyrazolecarbonitrile 73 with 3,4-dimethoxyphenyl isonitrile 74 and 2,4-dihydro-2-oxo-1H-benzo[d][1,3]oxazine-7-carbaldehyde 75 [35] (Scheme 17).

Scheme 17

In a recent report [36], 3-(benzylideneamino)-2-phenyl-5H-imidazo[1,2-b]pyrazole-7-carbonitriles 77 were synthesized, in moderate to high yields, from one-pot, four-component condensation reaction of aromatic aldehydes, toluene-4-sulfonylmethyl isocyanide, and 5-amino-1H-pyrazole-4-carbonitrile 73 in acetonitrile in the presence of p-toluenesulfonic acid as a catalyst at room temperature (Scheme 18).

Scheme 18

Similarly, A series of N-alkyl-2-aryl-5H-imidazo[1,2-b]pyrazole-3-amines 78 in good to high yields were synthesized by the three-component condensation of an aromatic aldehyde, aminopyrazole, and isocyanide in acetonitrile in the presence of 4-toluenesulfonic acid as a catalyst at room temperature [37] (Scheme 19).

Scheme 19

2.2. Syntheses of Imidazo[1,5-b]Pyrazole

2,3-Dihydroimidazo[1,5-b]pyrazoles 84 containing a structurally heterocyclic system corresponding to cyclized histamine were prepared by cyclodehydration of substituted N-(3-pyrazolylmethyl)acetamides 80 or N-(3-pyrazolylmethyl)acetamides 83, obtained by the catalytic hydrogenation of 1-benzoyl-4,5-dihydro-1H-pyrazole-3-carbonitriles 79 followed by acylation. These latter precursors 79 were conveniently obtained by the cycloaddition of substituted acrylonitriles with CH2N2 followed by in situ benzoylation using benzoyl chloride [48] (Scheme 20).

Scheme 20

2.3. Imidazo[4,5-c]Pyrazole

Recently, imidazo[4,5-c]pyrazoles 89 were synthesized in 65–96% yields by cyclization of -(4-halopyrazol-5-yl)amidine 88 under the conditions of copper-catalyzed cross-coupling reactions. Compound 88 was obtained via two pathways: (A) the reaction of 5-aminopyrazoles 25 with imidoyl chlorides 85 in dry 1,4-dioxane at room temperature and (B) the reaction of imino esters 87 with substituted aniline, followed by halogenations using either NBS in boiling acetonitrile or elementary iodine in the presence of KOH at room temperature [49] (Scheme 21).

Scheme 21

Nitrosation of compound 25 with sodium nitrite yielded the 4-nitrosopyrazoles 90, which were reduced to the diamines 91 with hydrazine hydrate in the presence of palladized charcoal. Since 91 were often unstable during the usual work-up for isolation, they were directly reacted with thiophosgene to give the isothiocyanatopyrazoles 94. Heating of 94 in pyridine gave the imidazo[4,5-c]pyrazole-5-thiones 95. In order to obtain 5-substituted derivatives imidazo[4,5-c]pyrazole-5-thiones 95 were reacted with iodomethane in sodium hydroxide to give 5-methylthio derivatives 96, which were subjected to hydrogen peroxide to yield 3-methyl-5-methylsulfonyl-1-phenylimidazo[4,5-c]pyrazoles 97. Compound 96 was submitted to hydrogenolytic desulfurisation in the presence of Raney nickel, thus producing 98. When heated at 200°C for 2 h, 5-amino-4-ethoxycarbonylaminopyrazole 92, obtained by treatment of 91 with ethyl chloroformate, afforded imidazo[4,5-c]pyrazole-5-one 93. The key step in the synthesis of 5-methylimidazo[4,5-c]pyrazole 102 was the intramolecular cyclodehydration in boiling pyridine of 5-ethylamino-4-nitrosopyrazole 101, which was prepared from 5-acylaminopyrazole 100. Reduction of 99 with LiAlH4 afforded the 5-alkylaminopyrazole 100. Nitrosation of 100 with amyl nitrite in the presence of hydrochloric acid yielded 101. Imidazo[4,5-c]pyrazoles 93, 95, 96, 97, 98, and 102, which were considered of interest as potential herbicides, were examined for the preemergence, postemergence, and posttransplant control of weeds in rice against broadleaf and grass weed species. Some imidazo[4,5-c]pyrazoles have potential herbicidal activity against a wide range of weeds, with 5-thiomethyl 96 and 5-unsubstituted derivatives being the most efficient. No herbicidal activity was observed in the 5-methylsulfonylimidazo[4,5-c]pyrazole 97 and imidazo[4,5-c]pyrazolone 93 series [50] (Scheme 22).

Scheme 22: Reagents: a, N; b, , Pd/C; c, CSC; d, reflux, pyridine; e, MeI; f, Raney Ni; g, ; h, ClCO2Et; i, heat at 200°C, 2 h; j, Ac2O; k, LiAlH4.

Similarly, imidazo [4,5-c] pyrazoles 106 were synthesized by acylation 5-aminopyrazoles 25 either with benzoyl chloride or with acetic anhydride to give 5-acylaminopyrazoles 103. Reduction of compounds 103 with LiAlH4 afforded the corresponding 5-alkylaminopyrazoles 104. Nitrosation of compounds 104 with amyl nitrite in the presence of hydrochloric acid yielded 5-alkylamino-4-nitrosopyrazoles 105. Cyclisation of compounds 105 to imidazo [4,5-c] pyrazoles 106 was achieved by heating 105 in boiling pyridine for 15–90 min [51] (Scheme 23).

Scheme 23

3. Syntheses by Annulation of the Pyrazole Ring onto an Imidazole Scaffold

3.1. Synthesis of Imidazo[1,2-b]Pyrazole

2,3-Dihydro-1H-imidazo[1,2-b]pyrazoles 112 and 113 were prepared by hydrazinolysis with 2,4-dinitrophenylhydrazine of ethyl 2-(1-(benzylideneamino)imidazolidin-2-ylidene)-2-nitroacetate 110 which was conveniently prepared from ethyl nitroacetate and N-benzylidene-2-(methylthio)-4,5-dihydro-1H-imidazol-1-amine 109 as described in Scheme 24 [52].

Scheme 24

3.2. Synthesis of Imidazo[1,5-b]Pyrazole

Dihydro-1H-imidazo[1,5-b]pyrazole-4,6(2H,5H)-dione 119 was synthesized from treatment 1-(benzylideneamino)-5-(2-hydroxyethyl)hydantoin 117, prepared from treated sodium salt of acetone semicarbazone 115 withα-bromo-γ-butyrolactone 116 and the reaction mixture was then subjected to acid hydrolysis followed by condensation with benzaldehyde, with SOCl2 to give 1-benzylidene-2,3,3a,4,5,6-hexahydro-4,6-dioxo-1H-imidazo[1,5-b]pyrazolium chloride 118. Next the latter salt was treated with MeOH and ether [53] (Scheme 25).

Scheme 25

3.3. Synthesis of Imidazo[4,5-c]Pyrazole

3-Amino-6-(β-D-ribofuranosyl)imidazo[4,5-c]pyrazole 125 was synthesized via an N–N bond formation strategy by a mononuclear heterocyclic rearrangement (MHR). Thus, 5-amino-1-(5-O-tert-butyldimethylsilyl-2,3-O-isopropylidene-β-D-ribofuranosyl)-4-(1,2,4-oxadiazol-3-yl)imidazole 123, synthesized from treatment of 5-amino-1-(β-D-ribofuranosyl)imidazole-4-carboxamide 122 with sodium ethoxideat room temperature followed by reaction with ethyl acetate at reflux temperature, underwent the MHR with sodium hydride in DMF or DMSO to afford the corresponding 3-acetamidoimidazo[4,5-c]pyrazole nucleosides 124 in good yields. Subsequent protecting group manipulations afforded the desired 3-amino-6-(β-D-ribofuranosyl)imidazo[4,5-c]pyrazole 125 as a 5:5 fused analog of adenosine. Compound 125 was evaluated for activity against two herpes viruses, herpes simplex virus type 1 (HSV-1) and human cytomegalovirus (HCMV), in a plaque reduction assay and an ELISA, respectively. Cytotoxicity was detected both in stationary human foreskin fibroblasts (HFF cells) and in growing KB cells. No activity was observed at the highest concentration tested (100 μM) against HCMV and HSV-1 [54] (Scheme 26).

Scheme 26: Reagents and conditions: (a) NH2OH, EtOH, reflux, 90 min, 70%; (b) (i) Na/EtOH, rt; (ii) MeCO2Et, EtOH, reflux; (c) NaH, DMSO, 75–100°C, 15 min, 124b: 74% from 123; (d) (i) NaH, DMF, 75–100°C, 15 min; (ii) TBAF, THF, 0°C, rt, overnight, 124a: 43% from 123; (e) (i) NaH, DMF, 75–100°C, 15 min; (ii) TBSCl, imidazole, cat. DMAP, DMF, rt, 8 h, 124b: 55% from 123.

4. Miscellaneous Methods

1,5-Dihydrazino-2,4-dinitrobenzene 126 was treated with -ketoesters to give 65–95% corresponding dihydrazones 127, which were subjected to reductive cyclization using PtO2 catalyst to provide benzo [1,2-b:5,4-]bis (1H-imidazo[1,2-b]pyrazoles 128 in 47–54% yields [55] (Scheme 27).

Scheme 27

Upon UV irradiation the substituted pyrrolo[2,3-d]-1,2,3-triazoles 129 (R = Me, Et; = Ph, substituted phenyl) were transformed toimidazo[4,5-c]pyrazoles 132 via intermediates 1,2,3,5-tetrazocine 130. X-ray crystal structure of 132 (R = Me, Ar = 4-BrC6H4) is reported [56] (Scheme 28).

Scheme 28

5. Conclusions

This review has attempted to summarize the synthetic methods, reactions, and medicinal application of imidazopyrazoles. Synthesis of imidazopyrazole derivatives may be via two categories: annulations of imidazole ring onto a pyrazole scaffold or annulations of pyrazole ring onto an imidazole scaffold.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publishing of this paper.

Acknowledgment

The authors would like to thank the Research Center of College of Engineering at King Saud University for supporting this work.

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