Facile synthesis of 1H-imidazo[1,2-b]pyrazoles via a sequential one-pot synthetic approach.

5-Aminopyrazole-4-carbonitrile and ethyl 5-aminopyrazole-4-carboxylate, as potential trifunctional building blocks are introduced in a facile, chemo- and regioselective multicomponent assembly of imidazo[1,2-b]pyrazoles via the Groebke-Blackburn-Bienaymé reaction (GBB reaction). Besides the synthetic elaboration of a green-compatible isocyanide-based access in three-component mode, we describe an operationally simple, one-pot two-step GBB protocol for the rapid construction of a 46 membered imidazo[1,2-b]pyrazole library with yields up to 83%.

Introduction

For the relatively rapid design and construction of a diverse, large pharmacophore library, the basic concepts of diversity-oriented synthesis and isocyanide-based multicomponent reactions, such as the Ugi four-component reaction (U-4CR), can be adopted. The sequential combination of four species (amines, aldehydes, isocyanides and carboxylic acids) in a single-pot synthetic operation permits access to bisamide peptidomimetics through a highly electrophilic nitrilium intermediate [1-4]. Modification of the conventional U-4CR protocol in three-component fashion by the incorporation of bifunctional 2-amino-substituted heterocycles provides an alternative route via an intramolecular N-trapping procedure, leading to various N,N-heterobicyclic systems [5-12]. A number of bifunctional 2-aminoazoles, including thiazole [13-14] and 1,3,4-thiadiazole [15-16] derivatives, or 2-aminoazine-based heterocycles, such as pyridines [17-19], pyrimidines [20-24] and pyrazines [25-27], have recently been utilized as Groebke–Blackburn–Bienaymé three-component reaction (GBB-3CR) inputs (Scheme 1).

Scheme 1

The conventional GBB-3CR.

The transformations of either the 5-aminopyrazoles [28-29], or their 4-substituted ethoxycarbonyl [7,30-32] and carbonitrile [28,33-36] analogues via the GBB-3CR have not been appreciably examined so far. In the relevant literature [7,28-2931-33], the products have predominantly been described as 5H-imidazo[1,2-b]pyrazoles with an endo double bond (and not as 1H-imidazo[1,2-b]pyrazoles), but without 2D NMR-based support. However, the GBB-3CR of functionalized pyrazoles might lead to the formation of two regioisomers [24] and four different tautomeric forms (5H- or 1H-imidazo[1,2-b]pyrazole with an endo- or exocyclic double bond) of each regioisomer. As presented [7,28-36], the “endo” 1H- and 5H-imidazo[1,2-b]pyrazoles were synthesized by the treatment of the corresponding amino substituted pyrazoles with aldehydes and isocyanides in the presence (5–30 mol %) of Lewis or Brønsted acid at ambient temperature or under heating (50–140 °C). The main disadvantages of this protocol involve long reaction times (3–18 hours) and requisite purification protocols (column chromatography and/or recrystallisation) besides limited diversity arising from the pyrazole starting material. As far as we are aware, a one-pot two-step process involving the in situ formation of the desired amino-substituted N-heterocycles such as C4 functionalized 5-aminopyrazoles, followed by GBB-3CR has not been described to date.

On the other hand, the imidazo[1,2-b]pyrazole core is definitely an attractive synthetic target, in view of its noteworthy pharmacological potential, which is strongly affected by the ring substitution pattern and the level of ring saturation. Among others, anti-inflammatory [37-38], antiviral [28,39] and antidiabetic [40] effects should be mentioned, besides the non-negligible cancer cell growth-inhibitory features of the corresponding compounds [30,34,41-42].

With respect to the current requirements of sustainable chemistry, our main aim was to design a streamlined and rapid green synthetic access route to a 1H-imidazo[1,2-b]pyrazole library in sequential one-pot protocol utilizing four components such as hydrazine hydrate, ethoxymethylene substituted malononitrile or ethyl cyanoacetate derivatives, isocyanides and aldehydes.

Results and Discussion

In the initial stage, a model GBB-3CR was performed between 5-aminopyrazole-4-carbonitrile (1a), p-tolualdehyde (2a) and tert-butyl isocyanide (3a) in order to elucidate the structure of the product and investigate the regioselectivity. The synthesis of 5-aminopyrazole-4-carbonitrile (1a) was based on a literature method [43-44].

A single product was observed in a yield of 59% during a reaction time of 15 min when a catalytic amount of HClO4 (20 mol %) was used as GBB-3CR promoter [7] in EtOH. 1D- and 2D NMR techniques (1H,13C-HSQC, 1H,13C-HMBC, 1H,1H-COSY and 1H,1H-NOESY) confirmed the exclusive presence of a 1H-imidazo[1,2-b]pyrazole core with an endocyclic double bond (6A), i.e., without the other possible regioisomeric and tautomeric forms 6B–H (Scheme 2, see Supporting Information File 1 for detailed data and spectra).

Scheme 2

Plausible products 6A–H.

For optimization, the 3CR synthesis of 6 was investigated under different catalytic conditions (Table 1). No reaction occurred in the absence of either a Brønsted or a Lewis acid catalyst (Table 1, entry 1). However, the use of Lewis acids, such as indium(III) salts or TMSCl, improved the reaction rate, with yields up to 67% (Table 1, entries 2–4). The GBB-3CR catalysed by Brønsted acids, including PTSA or HClO4, led to similar yields as on Lewis acid catalysis, though better results were obtained by using a catalytic amount of TFA in EtOH (Table 1, entries 5–7). From the aspect of an operationally simple green protocol, a mixture of water and EtOH as reaction medium yielded optimum results in terms of isolated yield, reaction time and mode of isolation (Table 1, entries 7–15). The one-pot 3CR of 5-aminopyrazole-4-carbonitrile (1a), p-tolualdehyde (2a) and tert-butyl isocyanide (3a) catalysed by TFA (20 mol %) in water/EtOH 1:1 furnished 6 isolated by simple filtration in a yield of 79% during 15 min.

Table 1

Solvent and catalyst screen of the GBB-3CRa.

Entry	Catalyst	Cat. load (mol %)	Solvent	Reaction time	Yield (%)
1	–	–	EtOH	> 72 h	0
2	In(OTf)3	20	EtOH	15 min	61b
3	InCl3	20	EtOH	15 min	67b
4	TMSCl	20	EtOH	15 min	64b
5	TsOH∙H2O	20	EtOH	15 min	52b
6	HClO4	20	EtOH	15 min	59b
7	TFA	20	EtOH	15 min	74b
8	TFA	20	CH2Cl2	15 min	35c
9	TFA	20	CH2Cl2	20 h	59b
10	TFA	20	CH2Cl2/MeOH 1:1	15 min	68b
11	TFA	20	MeCN	15 min	68b
12	TFA	20	THF	15 min	74b
13	TFA	20	MeOH	15 min	71b
14	TFA	20	H2O	15 min	63c
15	TFA	20	EtOH/H2O 1:1	15 min	79b
16	TFA	1	EtOH/H2O 1:1	36 h	46b
17	TFA	2	EtOH/H2O 1:1	20 h	62b
18	TFA	5	EtOH/H2O 1:1	1 h	75b
19	TFA	10	EtOH/H2O 1:1	25 min	76b

aReaction conditions: 1a (0.50 mmol), 2a (0.55 mmol), 3a (0.55 mmol), solvent (1 mL), room temperature. bIsolated yield after simple filtration. cIsolated yield after flash chromatography.

These results led us to envisage a sequential one-pot access to 1H-imidazo[1,2-b]pyrazole species through the in situ microwave-assisted formation of 1a followed by a GBB-3CR. A comparative study for the optimum synthesis of 6 revealed that the cyclocondensation of ethoxymethylene malononitrile (4a) with hydrazine (5) under microwave irradiation (80 °C, 150 W, 10 min, EtOH) proceeded with complete conversion (Scheme 3). It should be mentioned that the presence of water in this step resulted in a complex reaction mixture, moreover, the role of the reagent addition sequence was found to be crucial. The GBB reaction proceeded smoothly with acceptable efficacy during 15 min (overall yield of 6: 65%), with the addition of water, aldehyde 2a, a catalytic amount of TFA (20 mol %) and isocyanide 3a to the solution of the preformed 5-aminopyrazole-4-carbonitrile (1a) at room temperature.

Scheme 3

Synthesis of 6 via the sequential one-pot method.

The well-established sequential one-pot protocol was then adopted to synthetize a series of 1H-imidazo[1,2-b]pyrazoles from selected aldehydes 2a–j and isocyanide building blocks 3a–d (Table 2). Following the microwave-assisted rapid formation of 1a, the one-pot GBB reactions were completed during 10–60 min in yields of 23–83%. Unfortunately, limited substitution effect correlations could be established by employing aromatic aldehydes 2a–h. The introduction of electron-donating substituents such as 4-Me or 2,4,6-tri-OMe (derived from aldehydes 2a and 2h) resulted in similar conversions as for 2b, whereas the presence of two electron-withdrawing substituents as in 2e–g resulted in decreased yields. α-Methylcinnamaldehyde (2i) as an uncommon isocyanide-based MCR component was successfully subjected to the GBB reaction, leading to the formation of the corresponding bicycles 38–41 in yields of 26–67%. All the reactions except those based on pivalaldehyde (2j) provided access to 1H-imidazo[1,2-b]pyrazoles through simple filtration. Of the aliphatic isocyanides 3a–d applied, methyl isocyanoacetate (3c) often gave the lowest isolated yields, probably in consequence of self-trapping [45].

Table 2

Sequential one-pot GBB library generationa.

Entry	R1CHO	R2NC		Product	Yield (%)
1	2a	t-BuNC	3a	6	79b,c (65)c
2		t-octyl-NC	3b	7	66c
3		MeOOCCH2NC	3c	8	58c
4		CyNC	3d	9	75c
5	2b	t-BuNC	3a	10	68c
6		t-octyl-NC	3b	11	70c
7		MeOOCCH2NC	3c	12	70c
8		CyNC	3d	13	69c
9	2c	t-BuNC	3a	14	67c
10		t-octyl-NC	3b	15	71c
11		MeOOCCH2NC	3c	16	41c
12		CyNC	3d	17	74c
13	2d	t-BuNC	3a	18	63c
14		t-octyl-NC	3b	19	59c
15		MeOOCCH2NC	3c	20	35c
16		CyNC	3d	21	66c
17	2e	t-BuNC	3a	22	59c
18		t-octyl-NC	3b	23	39c
19		MeOOCCH2NC	3c	24	23c
20		CyNC	3d	25	46c
21	2f	t-BuNC	3a	26	59c
22		t-octyl-NC	3b	27	53c
23		MeOOCCH2NC	3c	28	28c
24		CyNC	3d	29	24c
25	2g	t-BuNC	3a	30	53c
26		t-octyl-NC	3b	31	41c
27		MeOOCCH2NC	3c	32	33c
28		CyNC	3d	33	46c
29	2h	t-BuNC	3a	34	70c
30		t-octyl-NC	3b	35	83c
31		MeOOCCH2NC	3c	36	48c
32		CyNC	3d	37	48c
33	2i	t-BuNC	3a	38	61c
34		t-octyl-NC	3b	39	67c
35		MeOOCCH2NC	3c	40	26c
36		CyNC	3d	41	63c
37	2j	t-BuNC	3a	42	50d
38		t-octyl-NC	3b	43	45d
39		MeOOCCH2NC	3c	44	47d
40		CyNC	3d	45	40d

aReaction conditions: 4a (0.50 mmol), 5 (0.55 mmol), ethanol (0.5 mL), MW (10 min, 80 °C, 150 W), then water (0.5 mL), 2a–j (0.55 mmol), TFA (0.10 mmol), 3a–d (0.55 mmol), room temperature, 10–60 min. bIsolated yield from the GBB-3CR. cIsolated yield after simple filtration. dIsolated yield after flash chromatography.

To create diversely substituted 1H-imidazo[1,2-b]pyrazoles, the sequential one-pot GBB method has been extended by means of ethyl 2-cyano-3-ethoxyacrylate (4b), (1-ethoxyethylidene) malononitrile (4c) and ethyl (E)-2-cyano-3-ethoxycrotonate (4d). Application of these starting materials in the optimized protocol with a slight modification (elevated temperature was necessary for the microwave assisted preformation of pyrazole intermediates 1b–d) afforded highly functionalized 1H-imidazo[1,2-b]pyrazole analogues 46–51 in yields of 54–79% (Table 3).

Table 3

Synthesis of highly substituted 1H-imidazo[1,2-b]pyrazolesa.

Entry	R1	R2	R3CHO	R4NC	Product	Yieldb (%)
1	H	COOEt	2a	3a	46	54
2	H	COOEt	2b	3b	47	56
3	Me	CN	2a	3a	48	79
4	Me	CN	2c	3c	49	57
5	Me	COOEt	2a	3a	50	74
6	Me	COOEt	2i	3b	51	59

aReaction conditions: 4b–d (0.50 mmol), 5 (0.55 mmol), ethanol (0.5 mL), MW (10 min; 4b: 150 °C, 4c,d: 120 °C; 150 W), then water (0.5 mL), 2a–c,i (0.55 mmol), TFA (0.10 mmol), 3a–c (0.55 mmol), room temperature, 10–60 min. bIsolated yield after simple filtration.

Conclusion

We have described here the development of a de novo and facile one-pot, two-step GBB method. The established protocol allowed the rapid synthesis of a 46-membered 1H-imidazo[1,2-b]pyrazole library with isolated yields up to 83%. Following the microwave-aided formation of functionalized 5-aminopyrazoles, the GBB-3CR transformations occurred during 10–60 min under mild conditions. This protocol offers operationally simple, green access to highly substituted 1H-imidazo[1,2-b]pyrazoles with easily variable substitution pattern and does not require complex purification techniques.

Experimental and characterisation data.