Ga(OTf)₃-promoted synthesis of functionalized 2-carbonyl-imidazo[1,2-a]pyridines derived from ethyl α-benzotriazolyl-α-morpholinoacetate

Abstract

An efficient route to the synthesis of 3-amino-2-ethoxycarbonyl imidazo[1,2-a]pyridine derivatives starting from ethyl α-benzotriazolyl-α-morpholinoacetate has been developed. By the reactions between primary heterocyclic amidines and isocyanides catalyzed by Ga(OTf)₃, target compounds were obtained in moderate to good yields. This in turn will set the stage for the wide application of this useful reaction for the synthesis of 3-amino-2-carbonylimidazo[1,2-a]pyridines based on imidazo[1,2-a]pyridine privileged structures.

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As a structural component of key bioactive molecules, fused imidazo[1,2-a]heterocycle moieties have been widely incorporated in the design of multiple biologically active agents.¹ Consequently, imidazopyridines, imdazopyrazines, and imidazopyrimidines in particular have been the focus of pharmaceutical investigations across a broad range of therapeutic areas.² The efficient synthesis of 3-amino-imidazo[1,2-a]azines via a reaction between a 2-aminoazine, an aldehyde and an isocyanide known as the Groebke–Blackburn–Bienaymé multicomponent reaction (GBB reaction)³ has triggered numerous efforts to develop libraries based on this drug-like core.^1a An analysis of the recent patent literature reveals that 3-amino-imidazo[1,2-a]azines have manifested themselves as ubiquitin ligase inhibitors (A),⁴ histone deacetylase inhibitors (B),⁵ skeletal muscle myosin modulators (C),⁶ potential antidiabetic SGLT1 inhibitors (D),⁷ angiogenesis inhibitors (E),⁸ modulators of sodium channels (F),⁹ and ligands for G-protein coupled receptors (e.g., PAR2, G)¹⁰ (Fig. 1).

Fig. 1 Therapeutic agents based on 3-amino-imidazo[1,2-a]azines.

Our continuing efforts aim to discover novel heterocycles as antitumor agents based on the imidazo[1,2-a]pyridine ring system,¹¹ which may be regarded as a privileged structure.¹² Following this strategy, our next challenge was the introduction of an additional 2-carboxy ester and 3-amino functionalities in the imidazo[1,2-a]pyridine framework, as shown in Scheme 1. 3-Amino-2-ethoxycarbonyl imidazo[1,2-a]pyridines and related compounds have also been described as potential antibacterial agents^2e and constitute valuable intermediates for the synthesis of purine derivatives.¹³ The Groebke reaction was first proposed to prepare this type of compound; in this case, glyoxylic acid or ethyl glyoxalate could be used as the carbonyl component and reacted with 2-aminopyridine and isocyanides to afford the target products. However, several papers have reported utilizing glyoxylic acid as an aldehyde source in Ugi-type MCR to afford only the decarboxylic 2-unsubstituted 3-amino imidazoazine.^12a,14 Nenajdenko et al. also reported that the reaction of ethyl glyoxalate as the carbonyl component of the Groebke reaction with 2-aminopyridines and isocyanides afforded the target product in around 30% yield with ethyl 2-aminoimidazo[1,2-a]pyridine-3-carboxylate isomer as the by-product (Scheme 1).¹⁵

Scheme 1 Proposed synthetic approach to 3-amino-2-ethoxycarbonyl imidazo[1,2-a]pyridines.

Ethyl α-Benzotriazolyl-α-morpholinoacetate (1) was reported to be a valuable synthon capable of reacting with different nucleophiles to form 3-amino imidazo heterocycles.¹⁶ Some preliminary studies by Bourguignon,¹⁶ Risch¹⁷ and Katritzky^18,19 have been very helpful for our purposes. The Mannich condensations of benzotriazole and ethyl glyoxalate with morpholine give the adduct ethyl α-benzotriazolyl-α-morpholinoacetate, which resulted in the reactive intermediate (4a) upon nucleophilic displacement of primary heterocyclic amidines (such as 2-aminopyridine). We supposed that this intermediate (4a) could react with isocyanides, possibly leading directly to 3-amino-2-ethoxycarbonyl imidazo[1,2-a]pyridines (Scheme 1).

The investigation was initiated by reacting ethyl α-benzotriazolyl-α-morpholinoacetate (1) with 2-aminopyridine in the presence of MeI to afford aminopyridine-substituted α-benzotriazolyl acetate 4a in good yield (85%). Subsequently, 4a was reacted with 4-methoxyphenyl isocyanide (2j) as the model substrate to optimize the reaction conditions (Scheme 2). The experiments were conducted to identify the best conditions in terms of catalyst, temperature and solvent; the results are summarized in Table 1. No reaction occurred in the absence of catalyst (Table 1, entry 1) or when TsOH or acetic acid was used as the catalyst (Table 1, entries 2 and 3). There was a moderate enhancement in yield when triflic acid was used as catalyst (Table 1, entry 4). Further catalyst screening indicated that Ga(OTf)₃ displays the highest catalytic activity toward the formation of 5a with an 78% yield (Table 1, entries 5–10). Furthermore, changing the solvent from THF to dioxane at a temperature of 100 °C increased the yield to 89% (Table 1, entries 11–14).

Scheme 2 Proposed reaction mechanism for the formation of 3-amino-2-ethoxycarbonyl imidazo[1,2-a]pyridines.

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst	Solvent	T (°C)	Time (h)	Yield^b (%)
a Reaction conditions: 4a (1 mmol), 2j (1.2 mmol), catalyst (1 mol%), solvent (3.0 mL), 65 to 100 °C.b Isolated yields.
1	—	THF	65	10	0
2	TsOH	THF	65	5	Trace
3	HOAc	THF	65	7	Trace
4	TfOH (3 mol%)	THF	65	3	35
5	Cu(OTf)2	THF	65	3	28
6	Sc(OTf)3	THF	65	3	60
7	Yb(OTf)3	THF	65	3	64
8	Ga(OTf)3	THF	65	3	78
9	InCl3	THF	65	5	40
10	ZnCl2	THF	65	5	35
11	Ga(OTf)3	EtOH	80	3	72
12	Ga(OTf)3	Toluene	100	4	60
13	Ga(OTf)3	CH3CN	80	4	65
14	Ga(OTf)3	Dioxane	100	2	89

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With the optimal conditions established, we then examined a series of reactions between isocyanides and substrate 4a to establish the scope and limitations of this process. The simplicity of this procedure is perfectly amenable to automation for combinatorial synthesis. Likewise, all the syntheses were performed on a parallel synthesizer (Radleys Discovery Technology, Carousel 12 Place Reaction Station) to give the corresponding products. Aliphatic (even sterically encumbered, Table 2, entries 1–6) and aromatic (electron-rich or electron-poor, Table 2, entries 7–9) isocyanides gave the corresponding products in moderate to good yields (ranging from 65–87%; Table 2). Consequently, we also examined the reactions of various 2-aminopyridines (3b–f) and 2-aminopyrazine (3g) with ethyl α-benzotriazolyl-α-morpholinoacetate, which proceeded smoothly and efficiently to produce the corresponding intermediates (4b–g) in excellent yields (step i, Table 3) followed by the reaction with 4-methoxyphenyl isocyanide (2a) to give the corresponding products (5k–p) in good yields (step ii, Table 3).

Table 2 Synthesis of 5a–i under optimized conditions^a

Entry	Isocyanides	Products	Yields^b (%)
a Reaction condition: 4a (1.0 mmol), 2a–i (1.2 mmol), Ga(OTf)3 (1 mol%), dioxane (3.0 mL), 100 °C, 2 h.b Isolated yields.
1			82
2			85
3			78
4			87
5			87
6			65
7			85
8			76
9			79

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Table 3 Synthesis of substrates 4b–g and products 5k–p under optimized conditions^a

Entry	Substrates	Products	Yield of step
			i^b	ii^b
a Reaction conditions: (i) 1 (1.0 mmol), 3b–g (1.0 mmol), CH3I (1.2 mmol), THF (3.0 mL); (ii) 4b–g (1.0 mmol), 2j (1.2 mmol), Ga(OTf)3 (1 mol%), doxane (3.0 mL), 100 °C, 2 h.b Isolated yields.
1			79	80
2			82	81
3			85	83
4			87	82
5			75	77
6			80	68

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On the basis of these preliminary results, the mechanism of these transformations was hypothesized, as shown in Scheme 2. Ethyl α-benzotriazolyl-α-morpholinoacetate (1) was methylated in situ to form the methyl morpholinium A. Subsequently, the N-methylmorpholinium group was replaced by 2-aminopyridine to afford substrate 4a followed by attacking by isocyanide to form intermediate B. A subsequent prototropic shift gave the final aromatic fused 3-aminoimidazole 5 (Scheme 2).

In summary, we provide a simple and straightforward synthesis of 3-amino-2-ethoxycarbonyl imidazo[1,2-a]pyridine-related compounds starting from ethyl α-benzotriazolyl-α-morpholinoacetate via the reaction with primary heterocyclic amidines and isocyanides catalyzed by Ga(OTf)₃. The protocol uses readily available starting materials, and the corresponding target products are obtained in moderate to good yields. Imidazo[1,2-a]pyridines are well-known as biologically and pharmaceutically active molecules; therefore, the present method will be widely applicable in organic and medicinal chemistry.

Experimental section

General

The ¹H-NMR (400 MHz) spectra were recorded using a high-performance digital FT-NMR with TMS as the internal standard. The ¹³C NMR (125 MHz) spectra were recorded using high-performance digital FT-NMR. LR-MS and HR-MS were obtained by ESI (positive ion mode) using a TOF mass analyzer. Purity was determined using high-performance liquid chromatography (HPLC) with the following conditions: ACN/H₂O eluent (containing 0.05% TFA) at a flow rate of 2 mL min⁻¹ flow at 40 °C, 5 min; gradient 5% ACN to 95% ACN; monitored by UV absorption at both 214 and 254 nm. TLC was carried out with glass pre-coated silica gel plates. TLC spots were visualized under UV light. All the solvents and reagents were used directly as obtained commercially unless otherwise noted.

Typical procedure for the synthesis of ethyl 2-(1H-benzo[d][1,2,3]triazol-1-yl)-2-(pyridin-2-ylamino)acetate (4a)

Methyl iodide (117 mg, 0.83 mmol) was added to a solution of ethyl 2-(benzotriazol-l-yl)-2-morpholinoacetate (1, 200 mg, 0.69 mmol) in dry THF. The mixture was stirred at 20 °C for 10 min, and 2-aminopyridine (3a, 65 mg, 0.69 mmol) was then added. The mixture was refluxed for 3 h, cooled at 20 °C and left for 16 h. The heterogeneous solution was filtered, and the resulting solution was evaporated in vacuum. The residue was purified by flash chromatography (petroleum ether–ethyl acetate 3 : 1) to give titled compound 4a as a white solid: yield, 174 mg (85%); mp, 110–120 °C; 1H NMR (400 MHz, CDCl₃) δ 8.10 (d, J = 4.9 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.51 (dd, J = 16.1, 8.0 Hz, 2H), 7.38 (dt, J = 15.4, 7.1 Hz, 2H), 6.69–6.64 (m, 1H), 6.61 (d, J = 8.3 Hz, 1H), 6.41 (d, J = 7.8 Hz, 1H), 4.30–4.23 (m, 2H), 1.16 (t, J = 7.1 Hz, 3H); LRMS (ESI): calcd for C₁₅H₁₆N₅O₂ (M + H): 298.12, found 298.15.

Typical procedure for the synthesis of ethyl 3-((4-methoxyphenyl)amino)imidazo[1,2-a]pyridine-2-carboxylate (5j)

To a solution of ethyl 2-(1H-benzo[d][1,2,3]triazol-1-yl)-2-(pyridin-2-ylamino)acetate (4a, 100 mg, 0.34 mmol), 4-methoxyphenyl isocyanate (2j, 54 mg, 0.4 mmol) in dioxane was added with Ga(OTf)₃ (35 mg, 0.07 mmol). The mixture was stirred at 100 °C for about 2 h. TLC showed that the starting materials were completely consumed. The reaction mixture was cooled to room temperature and concentrated under vacuum. The reaction mixture was poured into a mixture of dichloromethane (50 mL) and H₂O (25 mL). The organic layer was washed with water (2× 25 mL), dried, and concentrated in vacuum. The residue was purified by flash chromatography (SiO₂, petroleum ether–ethyl acetate 1 : 1) to give 5j as pale yellow solid: yield, 93 mg (89%); HPLC purity, 98%; mp, 153–155 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.63 (d, J = 9.4 Hz, 1H), 7.52 (d, J = 7.0 Hz, 1H), 7.19 (dd, J = 9.3, 6.8, 1.3 Hz, 1H), 7.10 (s, 1H), 6.84–6.79 (m, 2H), 6.72 (t, J = 6.9 Hz, 1H), 6.67–6.62 (m, 2H), 4.45 (q, J = 7.1 Hz, 2H), 3.77 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 164.23, 155.55, 140.42, 134.83, 132.35, 126.13, 124.22 (2× C), 119.70 (2× C), 118.87, 114.90 (2× C), 113.04, 61.23, 55.60, 14.45; HRMS (ESI) m/z calcd for C₁₇H₁₈N₃O₃ (M + H): 312.1348, found 312.1349.

Acknowledgements

This work was supported by the National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program,” China (no. 2012ZX09103-101-026, 2013ZX09507001, 2014ZX09508001) and the National Natural Science Foundation of China (grant 81473130, 81473092 and 81330076).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: General experimental procedures, compound characterization data, ¹H and ¹³C NMR spectra of new compounds. See DOI: 10.1039/c5ra02809d

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