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. 2019 Jul 8;7:457. doi: 10.3389/fchem.2019.00457

Development of Novel and Efficient Processes for the Synthesis of 5-Amino and 5-Iminoimidazo[1,2-a]imidazoles via Three-Component Reaction Catalyzed by Zirconium(IV) Chloride

Mohsine Driowya 1, Régis Guillot 2, Pascal Bonnet 1, Gérald Guillaumet 1,*
PMCID: PMC6628877  PMID: 31338360

Abstract

General and efficient approaches for the synthesis of new 5-amino and 5-iminoimidazo[1,2-a]imidazoles were developed through a three-component reaction of 1-unsubstituted 2-aminoimidazoles with various aldehydes and isocyanides mediated by zirconium(IV) chloride. The protocols were established considering the reactivity of the starting substrate, which varies depending on the presence of a substituent on the 2-aminoimidazole moiety. A library of new N-fused ring systems with wide structural diversification, novel synthetic, and potential pharmacological interest was obtained in moderate to good yields.

Keywords: multicomponent reactions, isocyanide Ugi reaction, zirconium(IV) chloride, catalysis, N-heterocycles, fused-ring systems, 2-aminoimidazole

Introduction

The development of innovative synthetic approaches that allow rapid access to a wide variety of new heterocyclic derivatives is of crucial interest. The use of multicomponent reactions (MCRs) offers significant advantages in organic synthesis, such as the combination of chemical transformations of three or more different starting materials in a one-pot procedure without isolating the intermediates (Dömling and Ugi, 2000; Dömling, 2006; Abdelraheem et al., 2017; Bariwal et al., 2018; Murlykina et al., 2018). In 1998, the groups of Groebke, Blackburn, and Bienayme simultaneously developed a new subclass of MCRs to produce a series of azine- and azole-fused aminoimidazoles, using diverse 2-aminoazines or 2-aminoazoles, aldehydes and isocyanides in the presence of Lewis or Brønsted acid catalysts (Bienayme and Bouzid, 1998; Blackburn, 1998; Groebke et al., 1998).

This reaction recently attracted much attention in organic and medicinal chemistry because of its simplicity, efficiency and the ability to generate diverse compound libraries (Devi et al., 2015; Kaur et al., 2016; Shaaban and Abdel-Wahab, 2016; Shaabani and Hooshmand, 2016).

The fused bicyclic 5-5 systems containing three nitrogen atoms with one in the bridgehead position are an important class of fused heterocyclic compounds in organic and medicinal chemistry due to their relevant biological properties, such as anti-cancer (Baviskar et al., 2011; Grosse et al., 2014; Sidduri et al., 2014; Meta et al., 2017), anti-viral (Elleder et al., 2012), anti-inflammatory (Bruno et al., 2007; Brullo et al., 2012), and anti-diabetic effects (Mascitti et al.). Our group has been involved over the last few years in the development of powerful tools for the synthesis of such systems (El Akkaoui et al., 2012; Grosse et al., 2012, 2013, 2014; Arnould et al., 2013; Tber et al., 2015a,b; Driowya et al., 2018). For instance, we very recently reported an efficient one-pot three component procedure for the synthesis of new functionalized imidazo[1,2-b]pyrazole derivatives in addition to a library of hitherto undescribed 7,7′-(substituted methylene)bis-imidazo[1,2-b]pyrazoles starting from 3-aminopyrazoles, various aldehydes and isocyanides, using a catalytic amount of perchloric acid or zirconium(IV) chloride (Driowya et al., 2018).

The imidazo-imidazole scaffolds hold a special place in this category, since they are found in compounds showing a wide range of pharmaceutical activities. In particular, they have been described as antifungal (Lila et al., 2003), antithrombotic (Imaeda et al., 2008; Fujimoto et al., 2009), anxiolytic and anti-depressive agents (Han et al., 2005; Tellew and Luo, 2008; Zuev et al., 2010). In addition, they have been reported as androgen receptor agonists and antagonists that are useful in the treatment of a variety of disorders (Zhang et al., 2006). Several synthetic methods based on multistep synthesis have been employed by our group and others to prepare these medicinally important N-fused imidazoles (Langer et al., 2001; Poje and Poje, 2003; Adib et al., 2008; Saima et al., 2012; Chen et al., 2013; Grosse et al., 2015; Castanedo et al., 2016; Loubidi et al., 2016; Kheder and Farghaly, 2017).

On the other hand, compounds containing an imidazo[1,2-a]imidazole moiety have been understudied (Compernolle and Toppet, 1986; Kolar and Tisler, 1995; Mas et al., 2002). Only one paper was found in the literature for the preparation of 5-aminoimidazo[1,2-a]imidazole compounds by MCRs starting from 1,5-disubstituted 2-aminoimidazoles (Pereshivko et al., 2013). However, the reported protocol gave poor to moderate yields and showed some limitations with 1-unsubstituted 2-aminoimidazole substrates. Hence, there is a need to develop a new, more efficient and general method for the preparation of these derivatives.

In this context, and in continuation of our ongoing search for innovative small molecules, we report herein novel and straightforward approaches for the synthesis of new series of 5-amino and 5-iminoimidazo[1,2-a]imidazoles starting from 1-unsubstituted 2-aminoimidazoles and using zirconium(IV) chloride as catalyst. To the best of our knowledge, this is the first report using 1-unsubstituted 2-aminoimidazoles in MCRs.

Results And Discussion

In order to find a MCR protocol that can afford an efficient formation of 5-aminoimidazo[1,2-a]imidazoles, we initially performed a model reaction using ethyl 2-aminoimidazole-4-carboxylate 1 with benzaldehyde and t-octyl isocyanide under different conditions (Table 1). Two possible regioisomers can be formed in this case 4a or 4a′ according on which side of the 2-aminoimidazole 1 that reacts.

Table 1.

Optimization of the reaction conditions.

Entrya Catalyst (mol%) Solvent Temp (°C) Heating method Time Yield (%)b
graphic file with name fchem-07-00457-i0001.jpg
1 ZrCl4 (5) MeOH r.t – 14 h 0c
2 ZrCl4 (5) EtOH 80 Conventional 14 h 12c
3 ZrCl4 (10) EtOH 80 Conventional 14 h 18c
4 ZrCl4 (10) EtOH 140 MW 10 min 38
5 ZrCl4 (10) n-BuOH 140 MW 10 min 62
6 ZrCl4 (10) PEG-400 140 MW 10 min 31
7 ZrCl4 (10) PEG-400 75 Conventional 4 h 77
8 ZrCl4 (5) PEG-400 75 Conventional 6 h 55
9 p-TsOH (10) PEG-400 75 Conventional 4 h 58
10 ZnCl2 (10) PEG-400 75 Conventional 7 h 23
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a

1 (1.0 mmol), benzaldehyde (1.1 mmol), t-octyl isocyanide (1.1 mmol), solvent (2 mL: entries 1–5; 1 mL: entries 6–10).

b

Yield of isolated product.

c

Starting materials were recovered.

The bold values represent the optimized conditions.

In our last study, we showed that the Lewis acid zirconium(IV) chloride delivered an efficient catalytic effect for the MCR (Driowya et al., 2018). This catalyst was therefore chosen for the present optimization study.

First, the reaction was carried out in methanol at room temperature in presence of 5 mol% of ZrCl4, but unfortunately, no product was observed (entry 1). Poor yields of the expected product 4a or 4a′ were obtained when the reaction was performed under heating in ethanol with either 5 or 10 mol% of ZrCl4 (entries 2 and 3). The reaction time was significantly reduced to 10 min under MW irradiation at 140°C, and the yield was relatively improved to 38% (entry 4). The use of n-BuOH as solvent instead of EtOH under MW irradiation resulted in an improvement of the yield to 62% (entry 5), whereas the use of PEG-400 gave a moderate yield (entry 6). Interestingly, the reaction in PEG-400 under classical heating at 75°C during 4 h provided a very good yield (entry 7). Moreover, the optimal amount of catalyst (10 mol%) was confirmed, since the use of 5 mol% resulted in a lower yield (entry 8). Finally, replacing ZrCl4 by other catalysts such as p-TsOH or ZnCl2 was associated with a significant decrease in the yield of the product 5-aminoimidazo[1,2-a]imidazole 4a or 4a′ (entries 9 and 10).

Hence, the optimized reaction conditions were found to be ZrCl4 (10 mol%) as catalyst and PEG-400 as solvent with heating at 75°C during 4 h. This system was used before for the preparation of imidazo[1,2-a]pyridines (Guchhait and Madaan, 2009).

In order to disclose the structure of the formed regioisomer of this reaction, we carried out a single-crystal X-ray analysis of the product (Figure 1). The results reveal the formation of the regioisomer 4a. The regioselectivity of this reaction can be explained by the presence of intermolecular hydrogen bonds on the ethyl 2-aminoimidazole-4-carboxylate 1, orienting the synthesis toward the formation of only the regioisomer 4a. Moreover, the structure of compound 4a is stabilized by intramolecular N-H…O and intermolecular N-H…N interactions as observed in the crystalline structure (see the crystallographic section on the Supplementary Material).

Figure 1.

Figure 1

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ORTEP representation of compound 4a.

With these reaction conditions in hand, we next explored the scope and limitation of our methodology with diverse 2-aminoimidazoles and isocyanides in the presence of a range of aldehydes as shown in Table 2. A large chemical library of 5-aminoimidazo[1,2-a]imidazole derivatives 4a–f and 5a–i was designed in generally good yields. The reactions proceeded well with both ethyl 2-aminoimidazole-4-carboxylate 1 and 4,5-dicyano-2-aminoimidazole 2. Unfortunately, no reaction was observed when employing the unsubstituted 2-aminoimidazole 3 as substrate, which was recovered after purification.

Table 2.

Synthesis of 5-aminoimidazo[1,2-a]imidazole derivatives 4a–f and 5a–i.

Entrya R1, R2 R3 R4 Product Yield (%)b
graphic file with name fchem-07-00457-i0002.jpg
1 CO2Et, H C6H5 t-octyl 4a 77 (62)c
2 CO2Et, H 4-MeOC6H4 t-octyl 4b 68
3 CO2Et, H 4-ClC6H4 t-octyl 4c 56
4 CO2Et, H 4-CF3C6H4 t-octyl 4d 71
5 CO2Et, H C6H5 t-butyl 4e 74
6 CO2Et, H C6H5 cyclohexyl 4f 59 (50)c
7 CN, CN C6H5 t-octyl 5a 67 (42)c
8 CN, CN 4-MeOC6H4 t-octyl 5b 65
9 CN, CN 2,4,6-MeOC6H2 t-octyl 5c 61
10 CN, CN 4-ClC6H4 t-octyl 5d 58
11 CN, CN 4-CF3C6H4 t-octyl 5e 76
12 CN, CN C2H5 t-octyl 5f 12 (5)c
13 CN, CN 3-Pyridyl t-octyl 5g 79
14 CN, CN 4-ClC6H4 t-butyl 5h 60 (54)c
15 CN, CN 4-ClC6H4 cyclohexyl 5i 47
16 H, H 4-MeOC6H4 t-octyl - 0 (0)c
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a

1, 2, or 3 (1.0 mmol), aldehyde (1.1 mmol), isocyanide (1.1 mmol), ZrCl4 (0.1 mmol), PEG-400 (1 mL), 75°C, 4 h (entries 1–6, 16) or 55°C, 2 h (entries 7–15).

b

Yield of isolated product.

c

Isolated yield using the conditions: ZrCl4 (10 mol%), n-BuOH (2 mL), MW (140°C), 10 min.

Moreover, the reaction occurred with electron-withdrawing and electron-donating substituents of the benzaldehydes, in addition to sterically hindered aldehydes (entry 9), aliphatic and heteroaromatic aldehydes (entries 12 and 13, respectively). However, a poor yield was obtained when using propionaldehyde (entry 12).

The impact of isocyanide on our reaction was also investigated; the tert-octyl isocyanide and tert-butyl isocyanide gave similar good results, whereas the cyclohexyl isocyanide showed slightly lower yields.

The MCR involving the unsubstituted 2-aminoimidazole 3 using our conditions did not yield any product. This can be explained by the poor reactivity of the starting substrate due to the absence of an electron-withdrawing group.

In order to find another strategy allowing us to synthetize 5-aminoimidazo[1,2-a]imidazoles starting from the unsubstituted 2-aminoimidazole 3, we first carried out the condensation of the latter with p-anisaldehyde as a first step model reaction under different conditions (Table 3). The free amine 3 was prepared from the commercially available 2-aminoimidazole sulfate (see Supplementary Material). Initially, conventional or MW heating of the reaction in different solvents with ZrCl4 (10 mol%) as catalyst provided the desired imine 6a in poor yields (entries 1–4). The use of ZnCl2 as catalyst furnished a very low yield (entry 5), while p-TsOH and InCl3 gave slightly higher yields (entries 6 and 7). Very interestingly, using a reduced catalytic amount of InCl3 (2 mol% instead of 10 mol%) under conventional or MW heating in ethanol produced a real improvement in terms of yield and reaction time (entries 9 and 11). This may explain the non-reactivity observed in the MCR (Table 2, entry 16), because of the instability of the formed imine under such acidic conditions. However, the prolonged reaction time noted with ZrCl4 (2 mol%) or when no catalyst was used, revealed the influence of InCl3 on this condensation reaction (entries 8 and 10, respectively).

Table 3.

Screening conditions for the synthesis of imine 6a.

Entrya Catalyst (mol%) Solvent Temp (°C) Heating method Time (h) Yield (%)b
graphic file with name fchem-07-00457-i0003.jpg
1 ZrCl4 (10) PEG-400 75 Conventional 16 31
2 ZrCl4 (10) n-BuOH 140 MW 2 22
3 ZrCl4 (10) Toluene 110 Conventional 16 15
4 ZrCl4 (10) EtOH 80 Conventional 16 24
5 ZnCl2 (10) EtOH 80 Conventional 16 5
6 p-TsOH (10) EtOH 80 Conventional 16 53
7 InCl3 (10) EtOH 80 Conventional 16 40
8 ZrCl4 (2) EtOH 80 Conventional 16 61
9 InCl3 (2) EtOH 80 Conventional 2 78
10 – EtOH 80 Conventional 30 60
11 InCl3 (2) EtOH 100 MW 1 75
12 InCl3 (2) n-BuOH 100 MW 2 59
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a

3 (0.5 mmol), p-anizaldehyde (0.55 mmol).

b

Yield of isolated product.

The bold values represent the optimized conditions.

After developing these optimized conditions for the first reaction step, we next focused on finding the best conditions for the second step, which is based on the [4+1] cycloaddition reaction of the formed imine with an isocyanide.

The resulting imine 6a was isolated and reacted with tert-octyl isocyanide under several catalytic conditions (Table 4). No reaction occurred when using the same conditions as for the condensation step (entry 1). Increasing the catalytic amount of InCl3 to 10 mol% produced the desired product in poor yields with either conventional or MW heating methods (entries 2 and 3). It is interesting to note that the 5-aminoimidazo[1,2-a]imidazole product formed was unstable and underwent a dehydrogenation reaction in situ to generate the corresponding stable oxidized compound 5-iminoimidazo[1,2-a]imidazole 7a. We already observed this type of oxidation in our previous work on the synthesis of imidazo[1,2-b]pyrazoles by MCRs (Driowya et al., 2018).

Table 4.

Screening conditions for the synthesis of 5-iminoimidazo[1,2-a]imidazole 7a.

Entrya Catalyst (mol%) Solvent Temp (°C) Heating method Time Yield (%)b
graphic file with name fchem-07-00457-i0004.jpg
1 InCl3 (2) EtOH 80 Conventional 14 h 0
2 InCl3 (10) EtOH 80 Conventional 6 h <5
3 InCl3 (10) EtOH 140 MW 10 min 14
4 p-TsOH (10) EtOH 140 MW 10 min 19
5 ZnCl2 (10) EtOH 140 MW 10 min 13
6 ZrCl4 (10) EtOH 140 MW 10 min 22
7 ZrCl4 (10) PEG-400 140 MW 10 min 26
8 ZrCl4 (10) n-BuOH 140 MW 10 min 40
9 ZrCl4 (10) n-BuOH 140 Conventional 3 h <5
10 ZrCl4 (5) n-BuOH 140 MW 10 min 31
11 InCl3 (10) n-BuOH 140 MW 20 min 25
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a

6a (0.2 mmol), tert-octyl isocyanide (0.22 mmol).

b

Yield of isolated product.

The bold values represent the optimized conditions.

The use of other catalysts such as p-TsOH, ZnCl2, and ZrCl4 under microwave irradiation did not produce any significant improvement in the reaction yield (entries 4–6). However, using ZrCl4 as catalyst and replacing EtOH by n-BuOH as solvent for the reaction showed a slight increase in the yield to 40% (entry 8), which was the optimum result obtained for this reaction. The same conditions used under conventional heating resulted in a significant decrease in the yield. The low yield and the difficulty of this reaction can be explained by the instability of the imine in the acid medium.

With these optimized conditions in hand, we succeeded in achieving the one-pot two-step procedure without isolating the imine by removing EtOH at the end of the first reaction step. The isolated product 7a was obtained with a global yield of 32%. This protocol was next extended to the synthesis of series of 5-iminoimidazo[1,2-a]imidazoles 7a–i starting from the unsubstituted 2-aminoimidazole and exploring a wide range of aldehydes and isocyanides (Table 5). As mentioned previously, the 5-aminoimidazo[1,2-a]imidazole products formed were unstable and led directly to the corresponding imine forms 7a–i. Despite the low yields obtained, it was nevertheless possible to produce the targeted compounds, which proved unsuccessful with the methods developed previously or with those cited in the literature.

Table 5.

One-pot two-step synthesis of 5-iminoimidazo[1,2-a]imidazole derivatives 7a–i.

Entrya R1 R2 Product Yield (%)b
graphic file with name fchem-07-00457-i0005.jpg
1 4-MeOC6H4 t-octyl 7a 32
2 C6H5 t-octyl 7b 24
3 2,4,6-MeOC6H2 t-octyl 7c 35
4 4-ClC6H4 t-octyl 7d 19
5 4-CF3C6H4 t-octyl 7e 13
6 C2H5 t-octyl 7f 16
7 3-Pyridyl t-octyl 7g 12
8 4-MeOC6H4 t-butyl 7h 17
9 4-MeOC6H4 cyclohexyl 7i 10
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a

3 (1.0 mmol), aldehyde (1.1 mmol), InCl3 (0.02 mmol), EtOH (10 mL), 2–4 h (90°C); isocyanide (1.1 mmol), ZrCl4 (0.1 mmol), n-BuOH (2 mL), 10 min (140°C).

b

Yield of isolated product.

The chemical space of our synthetized compounds was then enlarged, by removing the tert-octyl groups of 5-aminoimidazo[1,2-a]imidazoles 4a–d and 5a–g using TFA as cleavage agent in DCM and giving access to the primary amine compounds 8a–d and 9a–g, respectively, with yields ranging from 26 to 79% (Table 6). In a similar way, the primary imine imidazo[1,2-a]imidazoles 10a, 10b, 10d, 10e, and 10g were prepared in good yields from their corresponding Schiff base derivatives 7a, 7b, 7d, 7e, and 7g by deprotection of tert-octyl groups using the same conditions (Table 7). Unfortunately, the reaction was unsuccessful when the substituent R1 was 2,4,6-trimethoxyphenyl (entry 3) or ethyl (entry 6).

Table 6.

Cleavage of the t-octyl group of the products 4a–d and 5a–g.

Entrya R1 R2 R3 Product Yield (%)b
graphic file with name fchem-07-00457-i0006.jpg
1 CO2Et H C6H5 8a 70
2 CO2Et H 4-MeOC6H4 8b 74
3 CO2Et H 4-ClC6H4 8c 68
4 CO2Et H 4-CF3C6H4 8d 65
5 CN CN C6H5 9a 59
6 CN CN 4-MeOC6H4 9b 61
7 CN CN 2,4,6-MeOC6H2 9c 32
8 CN CN 4-ClC6H4 9d 57
9 CN CN 4-CF3C6H4 9e 79
10 CN CN C2H5 9f 41
11 CN CN 3-Pyridyl 9g 26
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a

4a–d, 5a–g (0.2 mmol), DCM/TFA 1:1 (5 mL), r.t.

b

Isolated yield.

Table 7.

Dealkylation of the t-octyl group of the products 7a–g.

Entrya R1 Product Yield (%)b
graphic file with name fchem-07-00457-i0007.jpg
1 4-MeOC6H4 10a 74
2 C6H5 10b 85
3 2,4,6-MeOC6H2 – –
4 4-ClC6H4 10d 82
5 4-CF3C6H4 10e 63
6 C2H5 – –
7 3-Pyridyl 10g 64
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a

7a–g (0.15 mmol), DCM/TFA 4:1 (5 mL), r.t.

b

Isolated yield.

Conclusion

In summary, we have designed highly efficient protocols of multicomponent isocyanide-based reactions catalyzed by zirconium(IV) chloride which offer the synthesis of a library of new functionalized 5-amino and 5-iminoimidazo[1,2-a]imidazoles in moderate to good yields. The optimized processes were successively applied to a large number of substituted (or unsubstituted) 2-aminoimidazoles, aldehydes and isocyanides. In addition, the use of inexpensive zirconium(IV) chloride as catalyst delivered an efficient catalytic effect for the reactions with a greater purity of isolated products compared to other catalysts.

Data Availability

All datasets generated for this study are included in the manuscript and/or the Supplementary Files.

Author Contributions

MD designed and performed the experiments, then was responsible for writing the manuscript. RG realised the X-ray analysis for the compound 4a. PB and GG directed the project and revised the manuscript.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

We acknowledge Région Centre-Val de Loire for financial support and Dr. Cyril Colas (ICOA, University of Orléans) for HRMS measurements of our products.

Supplementary Material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fchem.2019.00457/full#supplementary-material

Click here for additional data file. (8.2MB, pdf)

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Supplementary Materials

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Data Availability Statement

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