Letter pubs.acs.org/OrgLett
Metal-Free Cascade Approach toward Polysubstituted Indolizines from Chromone-Based Michael Acceptors Thomas Lepitre,†,‡ Raphael Le Biannic,†,‡ Mohamed Othman,†,‡ Ata Martin Lawson,*,†,‡ and Adam Daïch*,†,‡ †
UNILEHAVRE, FR 3038 CNRS, URCOM, Normandie Université, Le Havre, 76600, France EA 3221, INC3M CNRS-FR 3038, UFR des Sciences et Techniques, Université du Havre, BP: 1123, 25 rue Philipe Lebon, F-76063 Le Havre Cedex, France
‡
S Supporting Information *
ABSTRACT: An efficient cascade transformation toward indolizine-based molecules has been developed. This process leads to the rapid construction of two C−N bonds and one C−C bond without the need of any metal catalysis. The approach involves easily accessible chromone-based Michael acceptors and propargylamine derivatives as starting materials. This cascade constitutes a novel and very competitive alternative to the well reported strategies using pyridine or pyrrole derivatives for accessing the indolizine ring with substituents at uncommon C-positions.
S
Scheme 1. Classical Pyridine and Pyrrole Strategies for the Synthesis of Indolizines as Well as Our Approach from Chromone-Based Michael Acceptors
ince its discovery as a skeleton of high potential in medicinal chemistry, in particular for anticancer drug discovery, the indolizine ring, considered as a “biosteric” analogue of the popular indole, has largely expanded its scope of applications. Besides being classified today as a privileged medicinal scaffold1 displaying various important biological activities,2−7 the indolizine core has also shown more recently unique fluorescent8 and photophysical9 properties which offer new potential applications in imaging and electronic materials science. Moreover, some indolizine derivatives have also shown applications in the agricultural sector as herbicides10 and fungicides (Figure 1).11
more than 25% of the existing published work in this area, involves the construction of the pyridine ring from pyrrole derivatives (Scheme 1b).17,18 However, most of these reported methods suffer from major drawbacks such as the need of multistep synthesis of sophisticated substrates, weakly reactive in the pyridine case and sensitive in the case of pyrrole ring. In addition, they require in most of the cases, promoters of different kinds, including metals. To date, no direct approach using starting materials other than substituted pyridine or pyrrole has been reported. It also clearly appears that indolizines substituted at their C6- and/or C8position(s) are by far the least documented compared to the C1or C3-substituted indolizines. On the basis of these considerations, a rapid and efficient access to functionalized indolizines involving a cascade transformation from simple and cost-effective building blocks would be of high significant interest. The
Figure 1. Selected examples of indolizines with uses in different important sectors.
In light of these considerations, the great interest paid on this particular framework has led to substantial development of numerous methods for the rapid construction of the indolizine structure.12 However, all of the developed synthetic methods remain at least convergent and can be divided in two main approaches. The most common strategy is based on the construction of the pyrrole ring from pyridine often substituted at the N- or C2-position (Scheme 1a), which react in intramolecular or intermolecular fashion with electron-deficient alkynes,13,14 ketones,15 or alkenes.16 The second classical approach to reach the indolizine moiety, involved globally in © 2017 American Chemical Society
Received: February 19, 2017 Published: April 10, 2017 1978
DOI: 10.1021/acs.orglett.7b00309 Org. Lett. 2017, 19, 1978−1981
Letter
Organic Letters
Table 1. Optimization of the Cascade Process Conditionsa
significance of such an approach would be increased if (i) the resulting indolizines are obtained with high chemocontrol and (ii) could be functionalized at uncommon C-positions, thus offering new possibilities for indolizine diversification with promising biological profiles. Closely related to indolizines, only two approaches have been reported so far leading to these systems but fused to one or two carbacycles. In those cases, the bridgehead nitrogen atom of fused heterocycles is provided neither from pyridines nor from pyrroles. The first one involves imines or corresponding nitrones in chromone series reacting, respectively, with allenic esters (Scheme 1e)19 or enoxysilanes under Pd(II) catalysis (Scheme 1d).20 On the other hand, Wang et al. recently reported a microwave assisted multicomponent process for the construction of pyrazolo[3,4-e]indolizines derivatives (Scheme 1c).21 On the basis of both our previous reports22,23 and others’ contributions,24−26 the chromone-based Michael acceptor is a highly valuable platform for rapid access to molecules of biological potential such as pyridones,22 fused iso-oxazolines,23 pyridines,24 fused dihydropyridines25,26 and pyrazoles.26 In the present study, we used this platform to investigate the feasibility to access the indolizine skeleton. As illustrated in Scheme 1, a cascade process from enone of type 1 leads to pyridones via an ultimate amino-ester coupling reaction as a key step when R1 is a leaving group. We speculated that changes in the nature of the R1 group, for instance into enolizable ketone (CO)CH2R (point 3 in Scheme 1), would result in the interruption of the above intramolecular lactamic coupling, thus changing the course of the reaction. In addition, if amines bear an alkyne function with an electrophilic profile under catalytic activation (if needed), the process would lead ultimately to indolizines containing various substituents (Scheme 1f). To the best of our knowledge, an approach to synthesize indolizines starting from easily synthesizable Michael acceptors bearing the chromone core and propargylamine derivatives has no precedent in the literature. Our findings thus shed light on a novel utilization of chromonebased Michael acceptors in the field of diversity oriented synthesis (DOS).27 In addition, with up to five points available for indolizine diversification at uncommon C-positions, our approach clearly opens new avenues for QSAR studies. In the first set of our investigations, indolizine 2a was in fact synthesized in 57% yield in only 1 h by simply reacting the chromone-based Michael acceptor 1a with propargylamine as model substrates at 80 °C in toluene in the presence of 10 mol % of PdCl2 as catalyst (Table 1, entry 1). In the screening, we quickly observed that this cascade process could efficiently be performed without need of any metal assistance since neither the yield nor the reaction time were significantly affected by the absence of PdCl2 used formally to activate the triple bond (entry 2). Encouraged by these positive preliminary results, we then embarked upon the optimization of the cascade process. Due to its relatively low boiling point (83 °C), the use of 1.2 equiv of propargylamine resulted in increasing the yield to 60% (entry 3). The solvent effects were then checked, and interestingly only aprotic, nonpolar solvents afforded the expected product 2a in good yields (entries 3, 4, and 7), higher than 60% in all cases. With polar solvents, the process led to an important decrease of the isolated yields (entries 5, 6, 8, and 9). Finally, dichloroethane (DCE) afforded the best result (entry 7, 67%), and interestingly no correlation with dielectric constant (ε) values was observed, suggesting that the basicity of the latter may be also considered. Diversely substituted chromone-based Michael acceptors 1 were subjected to reaction with various propargylamine
entry c
1 2 3 4 5 6 7 8 9
solvent
dielectric constant ε
amine (equiv)
yield (%)b
toluene toluene toluene dioxane MeCN DMF DCE PEG EtOH
2.38 2.38 2.38 2.21 37.50 36.70 10.36 12.40 24.50
1.05 1.05 1.20 1.20 1.20 1.20 1.20 1.20 1.20
57 56 60 63 25 31 67 26 39
Reaction conditions: 1a (0.20 mmol) in 3 mL of solvent at 80 °C for 1 h. bIsolated yield. cPdCl2 (10 mol %) was used as metal catalyst.
a
derivatives. Interestingly, even though substitution of the phenol moiety was not anticipated to have a possible impact on the construction of the indolizine core, from a mechanistic point of view, electron-donating substituents generally provided better yields than electron-withdrawing ones. For instance, 3,4,5trimethoxychromone and para-substituted benzoyl chromone afforded the corresponding indolizines 2g and 2i, respectively, in 87% and 73% yield. On the other hand, para-bromo-substituted chromone led to indolizine 2f in only 45% yield and the nitro group firmly prevented the reaction. This pointed out the pivotal role of this substitution in the stabilization of pyridine intermediates favoring the formation of the pyrrole ring. α-Substituted propargylamines with diverse aryl group were suitable substrates for the cascade process favoring the final rearomatization step to access the indolizine skeleton. Functional groups of interest were also tolerated such as nitro group 2l, halogens (2k, 2m, 2o,) and even the polyaromatic hydrocarbons phenanthrene compound 2p, enriching structural diversity of the accessible and expected indolizines. Ultimately, terminal alkyne substitution impacted the efficiency of the cascade transformation since the obtained indolizines were accompanied by important ratios of complex mixtures of unidentified by-products (see limiting cases a and b, Scheme 2). In fact, by using a metallic catalyst such as PdCl2 following our first attempts of the cascade process optimization (Table 1, entry 1), the reaction in case of b proceeded quickly. The expected indolizine was seen in very small ratios despite the change in Scheme 2. Scope of Indolizine Based Frameworks
a
Traces of the desired compound were observed by 1H NMR spectroscopy. bCorresponding indolizines were obtained along with important ratios of unidentified products. 1979
DOI: 10.1021/acs.orglett.7b00309 Org. Lett. 2017, 19, 1978−1981
Letter
Organic Letters
alkynes.28 Further hydrogen transfer within zwitterion E and aromatization of F complete more favorably the formation of indolizines 2. As outlined in the plausible reaction mechanism (Scheme 4), 2-methyl-dihydropyridin-2-ol derivative C seems to be the important key intermediate in route to indolizines 2. In the case of Michael acceptors such as diethyl ketone, we speculated that the dehydration of 2-ethyl-dihydropyridin-2-ol of type C leading to 2u in only 50% yield (Scheme 3), would generate the 2ethylidene of type D in Z and/or E forms which cyclized with difficulty in a congested environment. To demonstrate the synthetic utility of our approach, a gram scale reaction was carried out with chromone 1k and 1-(2bromophenyl)-prop-2-yn-1-amine (Scheme 5). The obtained
reaction temperature but was accompanied by a high complexity of the crude reaction mixture making the separation false. In a last consideration, we turned our attention to the impact of Michael acceptor moiety (Scheme 3) on indolizine synthesis. Scheme 3. Impact of Michael Acceptors Diversification
a
Traces of competitive pyridine was observed in 1H NMR spectra. Only traces (
