Synthesis of Pyrrolo[2,1-a]isoquinolines by Multicomponent 1,3-Dipolar Cycloaddition

Pyrrolo[2,1-a]isoquinoline derivatives were synthesized by one-pot three-component reactions starting from isoquinoline, 2-bromoacetophenones and different non-symmetrical acetylenic dipolarophiles using 1,2-epoxypropane as solvent. The structure of the compounds was assigned by IR and NMR spectroscopy.

In this regard efforts were directed to synthesize aromatic or hydrogenated pyrrolo[2,1-a]isoquinoline frameworks in the search for molecules relevant for medicinal purposes. The synthesis and properties of the pyrrolo[2,1-a]isoquinolines were reviewed in 1997 by Mikhailovskii and Shklyaev [15], but the synthesis and characterization of these compounds is still of current interest, the proof being the important number of very recently reported papers [16][17][18][19].

Results and Discussion
Syntheses involving multicomponent one-pot reactions have provided useful synthetic tools in obtaining a wide variety of heterocyclic systems [35][36][37]. Thus a 1,3-dipolar cycloaddition targeting pyrrolo[2,1-a]isoquinoline derivatives, conducted as a one-pot three component process, seemed to be a very promising route. The key components of the one-pot three component reaction for the synthesis of pyrrolo[2,1-a]isoquinolines 4 (Table 1) are isoquinoline (1), the substituted bromoacetophenones 2, the non-symmetrical electron deficient alkynes 3 and 1,2-epoxypropane which acts both as solvent and proton scavenger (Scheme 1). Using this methodology the series of compounds listed in Table 1 was prepared in fair to good yields. The reaction mechanism (Scheme 2) for formation of the pyrroloisoquinolines 4 involves in the first step the generation of isoquinolinium N-ylides 6A by the action the isoquinolinium bromides 5 on the epoxide which, on nucleophilic ring opening by bromide anion, generates an alkoxide for deprotonation of the salt to form 6A. Subsequently, the 1,3-dipolar cycloaddition between the 1,3-dipole 6B and the unsymmetrical acetylenic dipolarophiles afford the corresponding primary cycloadducts 7 which undergoes a spontaneous in situ rearrangement and dehydrogenation leading to the fully aromatic compounds 4.
It is important to mention that no hydrogenated intermediates were isolated as for the previously reported two step procedure [27]. By comparison with the two step procedure the yields are appreciably lower but this minor inconvenience is significantly overcome by the more simple procedure and economy of both time and materials.
The structures of the new pyrroloisoquinolines were assigned by IR and NMR spectroscopy. The FT-IR spectra of the compounds present the characteristic bands for carbonyl groups that appear in the expected ranges, and the characteristic bands for the particular functional groups present in each example are also observed. On the basis of NMR data it was found that the cycloaddition reaction between isoquinolinium N-ylides and unsymmetrical dipolarophile is completely regioselective, as only one regioisomer was obtained. This is proven by the signal of the H-2 hydrogen which appears as a sharp singlet. In the 1 H-NMR spectra of compounds 4 the general characteristic features are the chemical shifts of atoms H-5, H-6 and H-10. The two protons in the pyridine moiety, namely H-5 and H-6, appear as two doublets with a coupling constant of 7.4 Hz. The H-10 hydrogen appears as a deshielded multiplet due to the spatial vicinity with the carbonyl group in the acetyl or ester groups. The 13 C-NMR spectra show all the expected signals. The most characteristic feature is the strong shielding observed for C-1 which appears at around 110 ppm as a consequence of its relative β position with respect to the pyrrole nitrogen. For the compounds 4a-c the carbon C-1 appears slightly deshielded to 118 ppm due to the influence of an acetyl group instead of an ester group. The carbon atoms in the carbonyl groups were observed in the expected ranges.

General
Melting points were determined on a Boëtius hot plate microscope and are uncorrected. The elemental analysis was carried out on a COSTECH Instruments EAS32 apparatus. The IR spectra were recorded on a FT-IR Bruker Vertex 70. The NMR spectra were recorded on a Varian Gemini 300 BB instrument, operating at 300 MHz for 1 H-NMR and 75 MHz for 13 C-NMR. Supplementary evidence was given by HETCOR and COSY experiments.

Conclusions
In conclusion, new pyrrolo[2,1-a]isoquinolines were obtained by a simple one-pot three component cycloaddition reaction starting from readily available materials. The structures of the new compounds were assigned by IR and NMR spectroscopy. The regioselectivity of the cycloaddition was deduced on the basis of 1 H-NMR data. The reaction is of potential interest due to importance of obtaining combinatorial libraries of compounds and due to the interest shown in the biological activity of compounds containing pyrrolo[2,1-a]isoquinoline skeletons.