Abstract
A transition metal-free domino Michael/SN2/aromatization annulation of 2-pyridylacetates with bromonitroolefins has been developed. A wide range of substrates containing various substituted groups was compatible with the present methodology and afforded functionalized indolizines with moderate to excellent yield (up to 99% yield). In addition, the potential practicality of the method stood out through scale-up reactions and further transformations to other valuable compounds. In our view, this study is an essential complement for the rapid construction of indolizine derivatives through a metal-free strategy.
Introduction
Nitrogen-containing heterocycles are important constituents in a diverse variety of leading compounds and drugs. Statistically, more than 85% of bioactive molecules are heterocycles; above all, the nitrogen atom heterocycle is one of the most frequently and privileged core backbones in their structures.1 Among them, indolizines are interesting unsaturated heterocycle compounds, which are made by a pyrrole ring and a pyridine ring, in which the nitrogen atom is shared by both rings. Many indolizine derivatives have shown a wide range of important biological activities (Figure 1), for example, anti-inflammatory (I),2 anticancer activity (II),3 vascular endothelial growth factor (VEGF) inhibitor (III),4 as well as phosphodiesterase V inhibitor (IV).5 Additionally, owing to indolizine derivatives possessing appreciable photophysical properties, they have also been investigated for organic light-emitting devices6 and biological fluorescent probes (V).7
Figure 1.
Selected bioactive molecules containing indolizine scaffolds.
Due to the unique bioactivity and physicochemical properties of indolizine derivatives, many methodologies for their synthesis have been developed by the organic chemistry community. Compared to classical methods, for example, the Scholtz and Chichibabin reactions,8 the main strategies for indolizine derivative synthesis also comprised C–H functionalization of pyridine at the C-2 position,9 cycloaddition reactions of pyridine analogues with electron-deficient unsaturated alkenes,9 carbonyl groups,10 transannulations of pyridotriazoles,11 pyrrole rings,12 and intramolecular cycloisomerization reactions (Scheme 1a).13 Despite the efficiency and practicality of these approaches, they suffer from shortcomings, more or less, such as higher reaction temperatures, limited substrate range, and the use of catalytic quantities and even stoichiometric metal compounds. In particular, the contamination of metal residues in biologically active indolizine derivatives requires extreme care during the purification process, which is tedious and environmentally unfriendly. Therefore, it is highly desirable to develop transition metal-free routes for the synthesis of various substituted indolizines.
Scheme 1. Synthetic Strategies for Indolizines and Our Design.
Nitroalkenes are a class of versatile building blocks in modern organic synthesis, which can be used to form diverse C–C and C–X bonds.14 In addition, owing to the bromine atom possessing strongly electronegative and the repulsion effect of its lone-pair electrons, the C=C of nitroalkene is easily polarized.15 So we believe that when introducing a bromine atom into nitroalkenes, bromonitroolefins exhibit different reaction paths compared with nitroalkenes. Recently, [2 + n] annulations with brominated nitroalkenes as dielectrophiles have been reported (Scheme 1b).16 On the other hand, the construction of indolizines through 2-alkylpyridines’ reaction with alkenes or alkynes is well established10 but often requires catalytic quantities and even stoichiometric metal compounds. Moreover, the inherent 1,3-dinucleophile features of 2-alkylpyridine could make it a type of useful C,N-dinucleophile that reacts with 1,n-dielectrophiles to access aza-heterocycles (Scheme 1c).17
Based on these achievements, coupled with our interest in constructing pharmacologically active indolizine derivatives, we envisioned that the [3 + 2] annulations of 2-alkylpyridines with α-brominated nitroalkenes might be carried out without a metal catalyst. In this work, we reveal a versatile method to synthesize poly-substituted indolizine compounds from 2-alkylpyridines with bromonitroolefins through cascade Michael/SN2/aromatization reactions without metal catalysts (Scheme 1d).
Results and Discussion
Consequently, our investigation started with methyl 2-pyridylacetate 1a and bromonitroolefin 2a as the starting substrates to obtain the optimal conditions, and the results are concluded (Table 1). Initially, we used organic bases as the promoters, such as DBU, Et3N, and DIPEA, which failed to promote the cascade Michael/SN2/aromatization reactions (Table 1, entries 1–3). Interestingly, we find that indolizine 3a can be isolated with a 64% yield under the presence of the inorganic compound Na2CO3 (Table 1, entry 4). And then, several other inorganic bases with different alkalis were tested, and Na2CO3 remained the best base. When NaHCO3, NaOAc, K2CO3, K3PO4, and Cs2CO3 were screened, the yields of indolizine 3a significantly dropped (Table 1, entries 5–9). The molar ratio of the reactant, which can adjust the value of the equilibrium constant K and affect the equilibrium state of the reaction, is very important in chemical synthesis for obtaining the target compounds with a high yield and purity.18 Thus, we further screen the molar ratio of 1a with 2a (Table 1, entries 10–11). When the molar ratio of 2a with 1a is 1:1.5, the indolizine compound 3a is obtained in a good yield of 75%. Moreover, a wide range of common solvents were examined to obtain the optimal reaction media (Table 1, entries 12–17). The results revealed that a protic polar solvent, such as MeOH, seemed to be inappropriate. Interestingly, the reaction can afford the targeted product with a slightly increased yield in the THF solvent (Table 1, entry 12 vs entries 13–17). Afterward, other reaction parameters, including the reaction temperature, the quantity of base, and concentration, were investigated. An outstanding yield was produced at higher temperatures (Table 1, entry 18), but further raising the reaction temperature to 100 °C could not improve the yield (Table 1, entry 19). In addition, either increasing or decreasing the amount of the base led to inferior results (Table 1, entries 20–21). Moreover, no improved result was obtained when the concentration was changed (Table 1, entry 22). At last, replacing the halogens with chlorine atoms also did not deliver better data (Table 1, entry 23). Overall, the optimal reaction condition is employing 2-alkylazaarene 1a (0.15 mmol), bromonitroolefin 2a (0.1 mmol), and Na2CO3 as a base (1.5 equiv) in THF (1.0 mL) at 80 °C for 24 h (Table 1, entry 18).
Table 1. Optimization of the Domino Reaction Conditionsa.
| entry | base | temp (°C) | solvent | yield (%)b |
|---|---|---|---|---|
| 1 | DBU | 60 | toluene | — |
| 2 | Et3N | 60 | toluene | — |
| 3 | DIPEA | 60 | toluene | — |
| 4 | Na2CO3 | 60 | toluene | 64 |
| 5 | NaHCO3 | 60 | toluene | 20 |
| 6 | NaOAc | 60 | toluene | 48 |
| 7 | K2CO3 | 60 | toluene | 18 |
| 8 | K3PO4 | 60 | toluene | 20 |
| 9 | Cs2CO3 | 60 | toluene | <5 |
| 10c | Na2CO3 | 60 | toluene | 75 |
| 11d | Na2CO3 | 60 | toluene | 70 |
| 12c | Na2CO3 | 60 | THF | 80 |
| 13c | Na2CO3 | 60 | dioxane | 53 |
| 14c | Na2CO3 | 60 | CH3CN | 15 |
| 15c | Na2CO3 | 60 | MeOH | <5 |
| 16c | Na2CO3 | 60 | DCM | 47 |
| 17c | Na2CO3 | 60 | acetone | 26 |
| 18c | Na2CO3 | 80 | THF | 86 |
| 19c | Na2CO3 | 100 | THF | 75 |
| 20c,e | Na2CO3 | 80 | THF | 35 |
| 21c,f | Na2CO3 | 80 | THF | 76 |
| 22c,g | Na2CO3 | 80 | THF | 81 |
| 23c,h | Na2CO3 | 80 | THF | 78 |
Unless noted otherwise, reactions were carried out with 1a (0.1 mmol), 2a (0.1 mmol), and base (1.5 equiv) in the solvent (1.0 mL) at 60 °C in a sealed tube for 12–24 h.
Isolated yields.
The equivalent ratio of 2a with 1a is 1:1.5.
The equivalent ratio of 1a with 2a is 1:1.5.
0.5 equiv of base.
2.5 equiv of base.
2.0 mL of the solvent.
The nitroolefin substrate is 2b.
Under the optimal catalytic conditions (Table 1, entry 18), we probed the scope of bromonitroolefins 2. As summarized in Scheme 2, it can be seen that a series of aryl (3b–3j), heteroaryl (3k–3m), and alkyl (3n) substrates were tolerated to the cascade Michael/SN2/aromatization reactions to afford indolizine derivatives. In general, the substrates containing a halogen or nitro at the ortho-position of the phenyl ring showed high reactivity and delivered the target products in higher yields (3b–3d). Moreover, the electron-donating group at the meta-position of the phenyl ring also provides the targeted indolizine product 3e in good yield. In addition, either electron-donating or -withdrawing groups at para-positions of phenyl ring also reacted smoothly with 2-alkylpyridine 1a, and the adducts 3f–3i were produced in good yield (80–88%). It is noteworthy that the 2,5-MeO-disubstituted substrates could generate the desired product 3j nearly equivalently. The 2-naphthyl substituted substrate 2k delivered the product 3k in a good yield. Further investigations demonstrated that the bromonitroolefin bearing S- and O-atom heteroaryl groups can also be used as the partner to react with methyl 2-pyridylacetate 1a to obtain products 3l and 3m in 78% and 87% yields, respectively. Intriguingly, a brominated nitroalkene including an alkyl group, for example, n-Bu, was also found to be a suitable nitroalkene in good yield for 48 h (3n, 79% yield), possibly due to its lower activity compared to an aryl group. Moreover, the relative configuration of the targeted indolizine 3a was unambiguously determined by X-ray crystallographic analysis; thus, the spare indolizine products were determined by analogy.
Scheme 2. Substrate Scope for the Domino Cyclization of 2-Alkylazaarene 1a with Bromonitroolefins.
Unless noted otherwise, reactions were carried out with 1a (0.15 mmol), 2a (0.1 mmol), and Na2CO3 (1.5 equiv) in THF (1.0 mL) at 80 °C in a sealed tube for 24 h.
Isolated yields.
The reaction time is 48 h.
Next, we also screened the scope of 2-alkylazaarenes under the optimal reaction conditions. At first, we investigated the different substituents on the ester moiety, and the results are listed in Scheme 3. Fortunately, the ester group could be converted into ethyl- or butyl-esters, all of which react well with α-brominated nitroalkene 2a to deliver their respective products 3o and 3p in good yield. A sterically hindered isobutyl, tert-butyl, or sec-amyl group (CH3(CH)CH2CH2CH3) on the ester was also compatible with the reaction to obtain the adducts 3q–3s in moderate to good yield (78%–88%). Moreover, with introduction of a CF3 functional group into the ester group, the corresponding product 3t was obtained in good yield. In addition, when using 2-(pyridine-2-yl)acetonitrile as the C,N-dinucleophile substrate to react with 2a, the indolizine targeted compound 3u was isolated with an 85% yield, although the time was extended to 48 h. Furthermore, it was found that the substrates bearing an electron-rich (Et) or electron-deficient (Br) group at the C5-position of the pyridine ring were also tolerated and delivered the indolizine targeted compounds 3v and 3w with good yields (86% and 84%), respectively. Additionally, when using ethyl 2-(isoquinolin-1-yl)acetate 2x as the C,N-dinucleophile, the π-extended indolizine compound 3x was generated in an excellent yield (95%). Ultimately, when the pyridine ring of the indolizine was changed to a pyrazine ring, the [3 + 2] annulation reaction also smoothly happened to give product 3y with a 96% yield.
Scheme 3. Substrate Scope for the Domino Cyclization of 2-Alkylazaarenes with Bromonitroolefin 2a.
Unless noted otherwise, reactions were carried out with 1a (0.15 mmol), 2a (0.1 mmol), and Na2CO3 (1.5 equiv) in THF (1.0 mL) at 60 °C in a sealed tube for 24 h.
Isolated yields.
The reaction time is 48 h.
To demonstrate the synthetic potential and utility of the cascade Michael/SN2/aromatization reactions, we conducted the domino reaction at a scale–up reaction under optimal reaction conditions. The result is exhibited in Scheme 4; the domino reaction was conducted on a gram-scale, generating the corresponding indolizine product 3a with an 84% yield, and there was no obvious loss of yield compared with the 0.1 mmol scale. Moreover, we also have an interest in evaluating the synthetic usefulness of these indolizines. Initially, we treated the 3a with diethyl acetylenedicarboxylate 4 at 90 °C with Cu(OAc)2 (20 mol %) under air in toluene, which resulted in the formation of pyrrolo[2,1,5-cd]indolizine 5 with a 61% yield as a result of the oxidative [8 + 2]-cycloaddition reaction. Furthermore, when 3w was subjected to the classical Suzuki–Miyaura coupling reaction, the coupling product 7 was smoothly delivered in a 73% yield under the catalyst Pd(PPh3)4 (10 mol %) at 80 °C. Compounds 5 and 7 possess a large conjugate group, which have the potential to be developed into fluorescent probes.
Scheme 4. Gram-Scale Experiment and Further Transformations.
Having explored the cascade multiple-step reaction, we were intrigued by the reaction mechanism. As illustrated in Scheme 5, based on the previous reports,10 a possible pathway for the synthesis of indolizine derivatives was proposed. At first, the cascade reaction started with a Michael addition of methyl 2-(pyridin-2-yl)acetate 1a to bromonitroolefin 2a to deliver intermediate A, and then intermediate A could further give B through tautomerization. Subsequently, intramolecular nucleophilic substitution led to the formation of intermediate C, which further upon elimination of the nitro group (free of one molecule of nitrite) delivered the target product 3a.
Scheme 5. Possible Reaction Pathway.
Conclusions
In conclusion, we herein report a highly efficient strategy for the construction of poly-substituted indolizine compounds from commercially accessible 2-pyridylacetates and bromonitroolefins. A wide range of substrates containing various substituted groups, including withdrawing or donating groups, were compatible under the present methodology and obtained the functionalized indolizines in moderate to excellent yield. Compared to previous reports, the merit of the present strategy includes transition metal-free catalysts, simple operation, excellent group tolerance, and a broad substrate scope. Meanwhile, the potential practicality of this method was identified by a gram-scale experiment and further transformations of the products to other valuable compounds. We think that this study is an important complement for the rapid synthesis of biologically indolizine derivatives through a metal-free strategy.
Experimental Section
General Procedure for Preparation of Indolizines 3a–3z
The reaction was performed with 2-alkylazaarenes 1 (0.15 mmol), bromonitroolefins 2 (0.1 mmol), and Na2CO3 (0.15 mmol) in THF (1.0 mL) at 80 °C for 24 or 48 h in a sealed tube. The reaction mixture was concentrated, and then the residue was subjected to column chromatography directly using petroleum ether/EtOAc (most use v/v = 8/1 to 4:1) as the eluent to afford the desired products 3.
Acknowledgments
We are grateful for the financial support from the High-Level Talent Research Start-up Fund Project of Guizhou Medical University, Guizhou Provincial Science and Technology Projects ZK[2023]-288, the High-Level Innovative Talent Training Program “Ten” Level Talents of Guizhou Province, the Platform Talent of Scientific Collaboration of Guizhou Province (No. GCC[2023]002), and the Hospital Research Foundation of Central Hospital of Guangdong Provincial Nongken (No. NKYY2023002).
Data Availability Statement
The data underlying this study are available in the published article and its Supporting Information.
Supporting Information Available
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.4c09295.
The authors declare no competing financial interest.
Supplementary Material
References
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Data Availability Statement
The data underlying this study are available in the published article and its Supporting Information.