Introduction

Pyrrolo[2,1-a]isoquinoline ring represents a key structural fragment of different alkaloids such as Erythrina-type alkaloids or compounds isolated from Carduus crispus L. The alkaloids of the Erythrina L. genus (Fabaceae) belong to the one of the most important series of pyrroloisoquinolines exhibiting various pharmacological properties including hypotensive, sedative, anticonvulsive, curare-like and anti-HIV-1 properties [1,2,3,4,5]. Also, the Erythrina extracts and isolated alkaloids demonstrate anxiolytic properties [6,7,8,9,10,11,12,13]. Moreover, Erythrina alkaloids activate GABAA receptors [14] and selectively inhibit nicotinic acetylcholine receptors, especially the receptors of α4β2 subtype [6, 15, 16]. The alkaloids Crispine A ( +) and Crispine B isolated from Carduus crispus L. have been tested for cytotoxic activity on the human cancer cell line. Crispine B showed significant cytotoxicity at micromolar levels [17]. In 2005, Jia et al. have discovered the antitumor activity of Crispine B on cancer cell lines HO-8901 (human ovarian neoplasm) (Fig. 1) [18].

Fig. 1
figure 1

Examples of Erythrina-type alkaloids and structures of Crispine A ( +), Crispine B

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The synthetic methods for the preparation of pyrrolo[2,1-a]isoquinolines are mainly based on two strategies: annulation of the pyrrole ring to the isoquinoline moiety or annulation of the isoquinoline core to the pyrrole or lactam cycle. When the formation of the pyrrolo[2,1-a]isoquinoline moiety proceeds via annulation on the pyrrole core, it is necessary to use palladium-catalyzed reactions, in particular the Mizoroki–Heck coupling reaction [19, 20]. For N-alkylated pyrroles, the intramolecular Heck reaction using Pd(PPh3)4 as a catalyst with sodium acetate as a base or Pd(PPh3)2Cl2 and Ph3P as a catalyst with potassium carbonate as a base allows to obtain pyrroloisoquinolines with good yields [21, 22]. There are also several effective approaches to the synthesis of the pyrrolo[2,1-a]isoquinolines’ frameworks based on the derivatives of butyrolactams [23,24,25,26].

The assembly of the pyrrolo[2,1-a]isoquinoline moieties based on the annulation of the pyrrole fragment to the isoquinoline core is a more common approach. One of the convenient methods includes the use of Morita–Baylis–Hillman carbonates with formal [3 + 2] cycloaddition reaction [27,28,29] that allows obtaining the biologically active ( ±)-Crispine A [27]. Another common method is the intramolecular cyclization of 1-propargyl and 1-allenyl-substituted tetrahydroisoquinolines. The formation of the pyrrole ring proceeds in the presence of silver acetate, and this approach was also used in the synthesis of the alkaloid Crispine A [30]. Intramolecular reactions of 1- and 1,2-functionalized tetrahydro-, 1,2- and 3,4-dihydroisoquinolines are often used for annulation of the pyrrole core [31,32,33,34,35,36]. Recently, our group has demonstrated the preparation of functionally substituted on the pyrrole ring pyrrolo[2,1-a]isoquinolines based on domino reactions of 3,4-dihydro-1-aroylisoquinolines with electron-deficient alkynes, α,β-unsaturated aldehydes and cross-conjugated vinyl ethynyl ketones [37,38,39,40].

Thus, continuing our research of the domino reactions with 3,4-dihydro-1-aroylisoquinolines, we tested conjugated ketones, nitroalkenes and nitriles as substrates. To the best of knowledge, the construction of annulated pyrrole cycle based on the reaction of iminoketones with the conjugated nitroalkenes or nitriles has not been previously described in the scientific literature.

Results and discussion

Starting benzoyl-, 4-chloro-, 4-fluoro-, 3,4-diethoxybenzoyl- isoquinolines 1a-d substituted at the C-1 atom were synthesized according to the published procedures [41, 42]. α,β-Unsaturated ketones (methyl vinyl ketone 2a, benzalacetone 2b, furfural acetone 2c, chalcones 2d,e, dibenzalacetones 2f,g), nitroalkenes 2h,i, acrylonitrile 2j, crotononitrile 2k and cinnamoyl nitrile 2l were used in the synthesis of pyrrolo[2,1-a]isoquinolines 3a-y (Scheme 1). Following the protocol developed by us for α,β-unsaturated aldehydes [39], initially, we screened the reaction of isoquinolines 1a-d with α,β-unsaturated ketones in trifluoroethanol under microwave activation. The interaction of 1-aroyl-3,4-dihydroisoquinolines 1a-d with methyl vinyl ketone 2a for 15 min at 150 °C gave the desired pyrrolo[2,1-a]isoquinolines 3a-d in moderate to good isolated yields (40–84% after the recrystallization from EtOAc–hexane mixture). To establish the effect of substituents on the course of the domino process, the isoquinolines 1a-d were reacted with benzal- (2b) and furfural-acetones (2c). The presence of the electron-donating aromatic substituent in the substrate 2b complicates the progress of the reaction in comparison with a methyl vinyl ketone. Wherefore the reaction was carried out under microwave activation at 160 °C for 120 min. Unfortunately, compounds 3e,f were isolated in the mixture with dehydrogenated 1b,d in a 2:1 ratio (3e,f; 47–50% yield). Interestingly, despite the harsh reaction conditions (160 °C), the desired pyrrolo[2,1-a]isoquinolines 3g,h, which contain a sensitive furane ring, were obtained in moderate yields (42% and 56%). It was also found that isoquinolines 1a,c do not react under reflux or under microwave activation with 2b,c yielding only the products of 1a,c aromatization.

Scheme 1
scheme 1

Scope of pyrrole[2,1-a]isoquinoline synthesis; ausing 10 mol% of AgOAc as catalyst (Supporting Information)

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Next, the reactions of 1-aroylisoquinolines with chalcones 2d,e and diarylideneacetones 2f,g were studied. We established that 1-aroylisoquinolines react differently with 2d-g. The reaction of 1-aroylisoquinolines 1b,d with chalcones 2d,e under microwave activation at 160 °C for a longer time (40–150 min) yields the expected pyrrolo[2,1-a]isoquinolines 3i-l in low to excellent yields (17–75%). The decreased yields of the desired product for chalcone 2e (3k,l were isolated in 17 and 20% yields, respectively) can be explained by the effect of the electron-donating methoxy group in the phenyl substituent, simultaneously increasing the time of reaction. To increase the yields of 3k,l, the reaction conditions were further optimized (see Schemes S1, S2 and Table S1 in the Supporting Information). As a result, we carried out reactions with 10 mol% AgOAc under microwave activation at 180 °C to obtain pyrrolo[2,1-a]isoquinolines 3k,l in 47% and 60%, respectively. In contrast, diarylideneacetones 2f,g react smoothly with 1-aroylisoquinolines 1b,d and with good yields. Apparently, the carbonyl group in these reagents responds to a much lesser extent to the presence of the aryl substituent.

The reactivity of nitroalkenes 2h,i with 1-aroylisoquinolines was studied on the example of drotaveraldine 1d and phenyl nitroalkene 2h in various alcohols. The use of microwave radiation led to low yields of the corresponding products. For EtOH or MeOH as solvents at reflux for 7–10 days, the yield of 3s was slightly lower than in TFE (2–3 days). Therefore, all reactions of 1-aroyl-3,4-dihydroisoquinolines 1b-d with nitroalkenes 2h,i were subsequently carried out only in trifluoroethanol. As a result, pyrrolo[2,1-a]isoquinolines 3q-v were obtained in 42–66% yields. Contrary to our expectations, the presence of methoxy donor group at the meta position in phenyl ring of nitroalkene did not have any effect on the yield as for the compounds 3k,l.

Then, conjugated nitriles have been screened in the reactions with 1-aroyl-3,4-dihydroisoquinolines. The reactions of isoquinolines 1b-d with acrylonitrile 2j were carried out in trifluoroethanol for 2–3 days at reflux, whereas the reactions under microwave activation led to a decreased yield of target compounds. Pyrrolo[2,1-a]isoquinolines 3w-y were formed in moderate to good yields (40–70%). But in comparison with nitro derivatives, the reaction with unsaturated nitriles has significant limitations. The reaction of 1a-d with crotononitrile 2k or with cinnamoyl nitrile 2l was tested not only under the above-described conditions, but also at reflux. Unfortunately, the desired products have not been detected.

The structures of the obtained pyrrolo[2,1-a]isoquinolines 3a-y were confirmed by 1H, 13C NMR and mass spectrometry.

The possible pathway for the reactions with conjugated ketones, nitroalkenes and acrylonitrile is proposed as illustrated in Scheme 2. Initially, the Michael-type zwitterion A is formed, whereupon the carbanion attacks the carbonyl group with subsequent five-membered ring closure (intermediate B). Next, the proton transfer occurs to give C, further dehydration of which leads to the ylide D, giving ultimately the products 3a-y.

Scheme 2
scheme 2

Proposed mechanism for the formation of pyrrolo[2,1-a]isoquinolines 3a-y

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Conclusion

Various 5,6-dihydropyrrolo[2,1-a]isoquinolines containing keto-, enone-, nitro-, and nitrile electron-withdrawing groups at C2-position can be obtained in moderate to good yields by a convenient protocol via a domino reaction of 1-aroyl-3,4-dihydroisoquinolines with conjugated alkenes. As far as we are aware, the synthesis of the annulated pyrrole ring via the interaction of the iminoketone fragment with nitroalkenes or acrylonitrile has never previously been reported. Selected α,β-unsaturated ketones contain more challenging groups than in our previous works. However, only in the case of reaction with methoxy chalcone derivative catalyst was used.