Concise and Free-Metal Access to Lactone-Annelated Pyrrolo[2,1-a]isoquinoline Derivatives via a 1,2-Rearrangement Step

Abstract

Here, An efficient approach to obtaining previously unknown furo[2′,3′:2,3]pyrrolo[2,1-a]isoquinoline derivatives from readily available 1-R-1-ethynyl-2-vinylisoquinolines is described. The reaction features a simple procedure, occurs in hexaflouroisopropanol and does not require elevated temperatures. It has been found that the addition of glacial acetic acid significantly increases the yields of the target spirolactone products. Using trifluoroethanol instead of hexaflouroisopropanol results in the formation of pyrido[2,1-a]isoquinolines.

1. Introduction

The γ-lactone moiety is present in many bioactive natural products isolated from various plants and fungal metabolites [1,2,3]. Compounds with lactone and spirolactone fragments are characterized by a broad range of bioactivities and find their application in the field of medicine and agriculture. Thus, trans-dehydrocrotonin exhibits hypolipidemic and hypoglycaemic properties and has anti-cancer activity [4,5,6,7]; tetranorditerpenoids can be used as herbicides [8]; dehydroleucodine has anti-inflammatory and antiulcer activities [9]; and Stemoamide, Stemonamine and Tuberostemospironine, being Stemona alkaloids, possess anti-inflammatory, insecticidal, antitussive activities (Figure 1) [2,10,11]. Lactonic pyrrolizidinone alkaloids—pyrrolizilactone and UCS1025A—demonstrate potent antibacterial and antitumor effects [3,12].

Due to having a wide profile of pharmaceutical activities, spirolactones attract considerable attention from scientists and advance both the development of simple and effective synthetic routes to such structures and the further study of their properties. Recently, numerous methods for the synthesis of spirolactones have been described in the literature [13,14,15,16]. Among a variety of known approaches, those that are based on mild, free-metal and step-economic reactions start from readily available materials and meet the requirements of modern and “advantageous” synthetic chemistry, and so deserve special attention. Domino processes, incorporating the rearrangement and reconstruction of the carbon skeleton and leading to the complexity of a molecule’s structure to be quickly revealed in one step, can be considered as eligible candidates, fitting all the requirements of “advantageous chemistry” [17].

2. Results and Discussion

Herein, we report a study devoted to elucidating the divergent transformations of 1-R-1-ethynyl-2-vinyl-substituted 1,2,3,4-tetrahydroisoquinolines 1a–g which occur in protic fluorinated solvents. One of the observed transformations proceeds via a 1,2-rearrangement step in the presence of AcOH/HFIP and opens up access to previously unexplored furo[2′,3′:2,3]pyrrolo[2,1-a]isoquinoline derivatives 3.

Previously, we have described the chemical behavior of 1-R-1-ethynyl-2-vinyl-substituted 1,2,3,4-tetrahydroisoquinolines in aprotic solvents [18]. It has been shown that the route of the MW-stimulated rearrangements deeply depends on the type of solvent used. The use of toluene favored the formation of pyrrolo[2,1-b][3]benzazepines, while switching to acetonitrile afforded pyrido[2,1-a]isoquinolines in good yields. Encouraged by these unusual results, we decided to examine the influence of protic solvents, particularly fluorinated alcohols—trifluoroethanol and hexafluoroisopropanol (HFIP)—on the disclosed rearrangements. Fluorinated alcohols are characterized by having a low nucleophilicity and high ionizing and solvating power, increased Brønsted acidity in the hydroxyl proton and high polarity, as well as the ability to affect the regio- and chemoselectivity of a reaction and its process rate [19,20,21,22]. In other words, they could open up new directions for these well-known transformations.

The initial 1-R-1-ethynyl-2-vinyl-substituted 1,2,3,4-tetrahydroisoquinolines 1a–g were obtained, according to a previously described procedure, from the corresponding 3,4-dihydroisoquinolines and methyl propiolate [18]. We began our study with transformations of tetrahydroisoquinolines 1a–g so it would arise in less acidic trifluoroethanol (pKa = 12.4) [19]. To our delight, the conversions did not require elevated temperatures and proceeded smoothly at 20 °C to generate pyrido[2,1-a]isoquinolines, in 55–95% yields, as the sole product (

Table 1. Synthesis of pyrido[2,1-a]isoquinolines 2a–g.

Entry	R	Product	Yield, %
1	Me	2a	95 a
2	i-Pr	2b	55
3	Bn	2c	56
4	Ph	2d	71
5	4-OMe-C6H4-	2e	79
6	4-F-C6H4-	2f	80
7	4-NO2-C6H4-	2g	68

^a 78% for reaction in C₂H₅OH.

). To understand what caused the change in the transformation route, the effect of the fluorinated alcohol or simply the presence of a protic solvent, we carried out a reaction of isoquinoline 1a with a non-fluorinated ethanol (pKa = 15.9) [19]. Substrate 1a was transformed into product 2a but the use of ethanol as a solvent slowed down the process three times; in addition, the yield of the target compound decreased to 78%. We have already reported on the synthesis of pyrido[2,1-a]isoquinolines from isoquinolines 1a–f in acetonitrile in the presence of triphenylphosphine [18]. In that case, the conversions required more severe conditions, which makes it less attractive compared to the present protocol.

Inspired by the results obtained in trifluoroethanol, we decided to explore the intramolecular changes when starting with tetrahydroisoquinolines 1a–g in more acidic hexafluoroisopropanol (HFIP) (pKa = 9.3) [19]. Using isoquinoline 1a as a model substrate, we performed a reaction at 20 °C. The transformation proceeded smoothly, but, to our surprise, led to a reaction mixture which consisted of lactonic pyrrolo[2,1-a]isoquinoline 3a (25%) and pyrido[2,1-a]isoquinoline 2a (71%) (

Table 2. Optimization of the reaction conditions.

Entry	glacial AcOH (Equiv.)	Yield 3a, %	Yield 2a, %
1	-	25	71
2	0.5	43	43
3	3.0	55	- a
4	5.0	56	- a

^a no traces of pyridoisoquinoline. Optimal conditions are bold in the table.

, entry 1). The formation of 3a was completely unexpected. The literature survey has not revealed the analogous structures, and we have succeeded only in finding isomeric ones [23]. It was clear that the acidity of the solvent played a key role. Given our earlier published studies demonstrating that the use of more acidic solvents such as HFIP and AcOH can alter the routes in the transformation of 1-R-ethynyl-decorated tetrahydroisoquinolines in reaction with activated alkynes towards more thermodynamically stable products, we considered that increasing the acidity of the medium with acetic acid would promote the construction of product 3a [24,25]. Indeed, the yield of the desired 3a was improved to 43% by adding 0.5 equiv of glacial acetic acid; however, the formation of compound 2a was still observed (Table 2, entry 2). The best result was achieved with 3.0 equiv of AcOH to produce lactone 3a with a 55% yield. It is noteworthy that a further increase in acetic acid did not have any significant effect on the yield of the target compound 3a (Table 2, entries 3 and 4).

With the optimized conditions in hand, we investigated the scope of the discovered transformation. To estimate the effect of the substituents attached at C-1 during the intramolecular changes to tetrahydroisoquinolines 1b–g, experiments with different alkyl and aryl substituents were carried out. Isoquinolines 1b–d with isopropyl, benzyl and phenyl groups proved to be good substrates for the transformation, producing lactonic pyrrolo[2,1-a]isoquinolines 3b–d in 50–64% yields (Scheme 1). However, the presence of substituents in the phenyl radical at C-1 affected both the composition and the ratio of the reaction mixtures. Thus, isoquinolines 1e–f containing electron-donating substituents (-OMe and -F) in the para-position in the phenyl ring provided pyrrolo[2,1-b][3]benzazepines 4 and 5; no traces of lactones were observed (Scheme 2). We have already published a paper describing the construction of the pyrrolo[2,1-b][3]azepines scaffold via [3,3]-sigmatropic rearrangement in vinyl- and ethynyl-substituted di(tetra)hydroisoquinolines [18], but again the present version of the reaction stood out due to its simplicity and mild reaction conditions. para-Nitrophenyl-substituted isoquinoline 1g produced a mixture of products, consisting of pyrido[2,1-a]isoquinoline 2g (47%), 1-ylidene pyrrolo[2,1-a]isoquinoline 6b (19%) and lactone 3g (13%) (Scheme 1).

The structure of 1-ylidene pyrrolo[2,1-a]isoquinoline 6b was assigned on the basis of NOESY, HMQC and HMBC spectra (Figure 2, see Supporting Information, Figures S1–S3). The NOESY spectrum has correlations between H-1 and H-3 in the pyrrole cycle as well as between H-1 and H-5 and H-10 in the isoquinoline moiety. In the HMBC spectrum, there are correlations between H-1 and C-1, C-3, C-10b in the pyrrole cycle; C-5, C-2 in the ester group; and C-6 in the aryl substituent.

Catalytic routes towards lactones where HFIP facilitates the formation of the products [26,27] which are known in the literature. We believe that the transformation commences with the HFIP-assisted polarization of the enamine moiety (Scheme 3). The subsequent formation of the pyrrole ring (A) followed by the migration of a proton from the solvent to the anionic center of the ylidene fragment results in an intermediate (B). The following [1,3]-shift gives cation (C) in which a Wagner–Meerwein rearrangement occurs to furnish the intermediate (D). The final lactonization of the latter leads to the formation of the target products 3.

The ambiguous behavior of isoquinolines in HFIP in the presence of 3.0 equiv of acetic acid returned us to the idea of carrying out these reactions without any additives. At 20 °C in HFIP, isoquinolines 1a–g formed multicomponent mixtures, from which the products were isolated using column chromatography. As was expected in the case of the starting compounds 1b–d with isopropyl, benzyl and phenyl substituents, the yields of lactones 3 decreased (Scheme 1). But again, the isoquinolines 1e–g decorated with para-OMe, para-F and para-NO₂ phenyl radicals at C-1 stood out from the general scheme. Now, isoquinolines 1e–f having electron-donating groups demonstrated the highest yields of the desired lactone 3. The formation of lactone 3e was accompanied by the formation of product 6a—1-ylidene-substituted pyrrolo[2,1-a]isoquinolines—with a 15% yield (Scheme 1). In the case of isoquinoline 1g with the para-NO₂ phenyl radical, we did not find the corresponding lactone 3g; from the reaction mixture we obtained, pyrido[2,1-a]isoquinoline 2g and 1-ylidene-pyrrolo[2,1-a]isoquinoline 6b were isolated with 43% and 31% yields, respectively (Scheme 1).

3. Materials and Methods

3.1. General Information

IR spectra were recorded on an Infralum FT-801 FTIR spectrometer on KBr tablets for crystalline compounds or on a film for amorphous compounds (ISP SB RAS, Novosibirsk, Russia). ¹H and ¹³C NMR spectra were acquired on a 600 MHz NMR spectrometer (JEOL Ltd., Tokyo, Japan) from CDCl₃ to acquire compounds with a solvent signal as the internal standard (7.27 ppm for ¹H nuclei, 77.2 ppm for ¹³C nuclei); peak positions were given in parts per million (ppm, δ). Multiplicities are indicated by s (singlet), d (doublet), t (triplet), m (multiplet). Coupling constants, J, are reported in Hertz. HRMS spectra were recorded on an AB SCIEX TripleTOF 5600+ mass-spectrometer (AB Sciex Pte. Ltd., Singapore) using electrospray ionization (ESI). The measurements were conducted in a positive-ion-mode mass range from m/z 100 to 1000. A syringe injection was used for solutions in MeOH (concentration 100 ng/mL, flow rate 100 μL/min). Melting points were determined on SMP-10 apparatus (Bibby Sterilin Ltd., Stone, UK) with open capillary tubes. Sorbfil PTH-AF-A-UF plates (Imid Ltd., Krasnodar, Russia) were used for TLC; visualization was carried out in an iodine chamber or using KMnO₄ and H₂SO₄ solutions. Silica gel (40–60 μm, 60 Å) from Macherey-Nagel GmbH&Co (Loughborough, UK) was used for column chromatography. All reagents (Sigma-Aldrich, St. Louis, MO, USA; Merck, Darmstadt, Germany; J.T. Baker, Phillipsburg, NJ, USA) were used without additional purification. Compounds 1a–f, 2a–f and 4 were also prepared earlier according to the described procedures [18].

Deposition Number 2156399 (for 3a) contains the supplementary crystallographic data for this paper. These data are provided free of charge by the joint Cambridge Crystallographic Data Centre and Fachinformationszentrum Karlsruhe Access Structures service (see Supporting Information, Table S1).

3.2. General Procedure for the Synthesis of Compound 1g

Methyl propiolate (3.0 mmol) was added to the solution of corresponding isoquinoline (1.0 mmol) in 7 mL of CH₂Cl₂. The reaction was carried out at room temperature. The progress of the reaction was monitored by TLC (Sorbfil, EtOAc-hexane, 1:1). The solvent was removed under reduced pressure; in the case of compound 1g, the residue was purified by column chromatography on silica gel (1:5 EtOAc–hexane).

• Methyl (2E)-3-[6,7-dimethoxy-1-(3-methoxy-3-oxoprop-1-yn-1-yl)-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl]prop-2-enoate (1g). Yield 0.397 g (83%), yellow oil. IR spectrum (KBr), υ/cm⁻¹: 2231 (C$\equiv$
• C), 1717 (C=O), 1519, 1349 (NO₂). ¹H NMR (600 MHz, CDCl₃) δ 8.23–8.21 (m, 2H, H-Ar), 7.68–7.66 (m, 2H, H-Ar), 7.36 (d, J = 13.6 Hz, 1H, -CH$=$
• CH-CO₂Me), 6.65 (s, 1H, 8-CH), 6.39 (s, 1H, 5-CH), 4.94 (d, J = 13.6 Hz, 1H, -CH$=$
• CH-CO₂Me), 3.88 (s, 3H, OCH₃), 3.82 (s, 3H, OCH₃), 3.67 (s, 3H, OCH₃), 3.66–3.63 (m, 1H, 3-CH₂), 3.62 (s, 3H, OCH₃), 3.49–3.46 (m, 1H, 3-CH₂), 3.09–3.05 (m, 1H, 4-CH₂), 2.95–2.92 (m, 1H, 4-CH₂). ¹³C NMR (150 MHz, CDCl₃) δ 169.0, 153.4, 149.3, 149.0, 148.8, 148.5, 148.0, 128.6 (2C), 127.2, 125.6, 124.3 (2C), 111.2, 111.1, 92.8, 84.7, 80.5, 64.3, 56.2, 56.1, 53.2, 51.1, 42.8, 27.9. HRMS (ESI) m/z calc’d for C₂₅H₂₄N₂O₈ [M+H]⁺ 481.1605, found: 481.1605 (0.0 ppm).

3.3. General Procedure for the Synthesis of Compounds 2a–g

Isoquinolines 1a–g (0.3 mmol) were dissolved in 2,2,2-trifluoroethanol (7 mL). The reaction was carried at room temperature. The progress of the reaction was monitored by TLC (Sorbfil, EtOAc-hexane, 1:1). The solvent was removed under reduced pressure, the residue was crystallized from Et₂O to produce compounds 2a, 2c–f; in the case of compounds 2b and 2g, the residue was purified by column chromatography on silica gel (1:5 EtOAc–hexane). Yields of 2a–f in 2,2,2-trifluoroethanol: 2a (95%), 2b (55%), 2c (56%), 2d (71%), 2e (79%), 2f (80%). The spectral data for compounds 2a–f are similar to those previously obtained and reported in [18].

• Dimethyl 11b-(4-nitrophenyl)-9,10-dimethoxy-7,11b-dihydro-6H-pyrido[2,1-a]isoquinoline-2,3-dicarboxylate (2g). Yield 0.098 g (68%), light yellow oil. IR spectrum (KBr), υ/cm⁻¹: 1688 (C=O), 1519, 1347 (NO₂). ¹H NMR (600 MHz, CDCl₃) δ 8.10 (d, J = 8.8 Hz, 2H, H-Ar), 7.81 (s, 1H, 4-CH), 7.54 (s, 1H, 1-CH), 7.27–7.25 (m, 2H, H-Ar), 7.01 (s, 1H, 11-CH), 6.67 (s, 1H, 8-CH), 3.90 (s, 3H, OCH₃), 3.76 (s, 6H, 2*OCH₃), 3.60–3.56 (m, 1H, 6-CH₂), 3.39 (s, 3H, OCH₃), 3.34–3.30 (m, 1H, 6-CH₂), 3.00–2.96 (m, 1H, 7-CH₂), 2.80–2.77 (m, 1H, 7-CH₂). ¹³C NMR (150 MHz, CDCl₃) δ 167.0, 164.3, 161.2, 156.0, 149.1, 147.8, 147.6, 147.2, 129.4 (2C), 126.2, 126.1, 123.1 (2C), 112.3, 111.3, 105.7, 104.1, 78.7, 56.1, 55.9, 51.1, 51.0, 42.4, 29.2. HRMS (ESI) m/z calc’d for C₂₅H₂₄N₂O₈ [M+Na]⁺ 503.1425, found: 503.1421 (−0.8 ppm).

3.4. General Procedure for the Synthesis of Compounds 3a–g, 4, 5a,b and 6a,b

(A) Isoquinoline 1 (0.3 mmol) was dissolved in 7 mL HFIP. The reaction was carried out at room temperature. The progress of the reaction was monitored by TLC (Sorbfil, EtOAc-hexane, 1:1). The solvent was removed under reduced pressure, the residues were chromatographed on silica gel (1:3 EtOAc–hexane) to obtained compounds 3a–g and 6a,b.

(B) To a solution of isoquinoline 1 (0.3 mmol) in 7 mL HFIP, glacial AcOH (0.9 mmol) was added. The reaction was carried at room temperature. The progress of the reaction was monitored by TLC (Sorbfil, EtOAc-hexane, 1:1). The solvent was removed under reduced pressure; compounds 3a–g, 4, 5a,b and 6b were chromatographed on silica gel (1:5 EtOAc–hexane (for 4 and 6a,b); 1:3 EtOAc–hexane (for 3a–g, 5a,b)).

• Methyl 10,11-dimethoxy-3a-methyl-2-oxo-3,3a,7,8-tetrahydro-2H-furo[2′,3′:2,3]pyrrolo[2,1-a]isoquinoline-4-carboxylate (3a). Yield 0.059 g (55%), white solid, mp 210–212 °C. IR spectrum (KBr), υ/cm⁻¹: 1764, 1680 (C=O). ¹H NMR (600 MHz, CDCl₃) δ 7.19 (s, 1H, 5-CH), 6.69 (s, 1H, H-Ar), 6.60 (s, 1H, H-Ar), 3.90 (s, 3H, OCH₃), 3.87 (s, 3H, OCH₃), 3.70 (s, 3H, OCH₃), 3.68–3.60 (m, 2H, 7-CH₂), 3.52 (d, J = 18.2 Hz, 1H, 3-CH₂), 2.90 (d, J = 18.2 Hz, 1H, 3-CH₂), 2.90–2.85 (m, 1H, 8-CH₂), 2.74–2.70 (m, 1H, 8-CH₂), 1.03 (s, 3H, CH₃). ¹³C NMR (150 MHz, CDCl₃) δ 174.9, 164.6, 150.0, 148.3, 146.5, 129.0, 122.4, 111.5, 109.2, 108.4, 104.9, 56.4, 56.0, 54.1, 50.8, 42.8, 40.5, 29.8, 21.6. HRMS (ESI) m/z calc’d for C₁₉H₂₁NO₆ [M+H]⁺ 360.1442, found: 360.1451 (2.5 ppm).

• Methyl 10,11-dimethoxy-2-oxo-3a-(propan-2-yl)-3,3a,7,8-tetrahydro-2H-furo[2′,3′:2,3]pyrrolo[2,1-a]isoquinoline-4-carboxylate (3b). Yield 0.081 g (50%), white solid, mp 237–239 °C. IR spectrum (KBr), υ/cm⁻¹: 1751, 1675 (C=O). ¹H NMR (600 MHz, CDCl₃) δ 7.35 (s, 1H, 5-CH), 6.67 (s, 1H, H-Ar), 6.62 (s, 1H, H-Ar), 3.90 (s, 3H, OCH₃), 3.88 (s, 3H, OCH₃), 3.79 (d, J = 17.9 Hz, 1H, 3-CH₂), 3.68 (s, 3H, OCH₃), 3.66–3.64 (m, 2H, 7-CH₂), 2.98–2.93 (m, 1H, 8-CH₂), 2.95 (d, J = 17.9 Hz, 1H, 3-CH₂), 2.75–2.71 (m, 1H, 8-CH₂), 1.85–1.79 (m, 1H, CH(CH₃)₂), 0.98 (d, J = 6.7 Hz, 3H, CH(CH₃)₂), 0.43 (d, J = 6.7 Hz, 3H, CH(CH₃)₂). ¹³C NMR (150 MHz, CDCl₃) δ 174.6, 165.3, 150.1, 148.7, 148.1, 128.9, 122.4, 111.5, 109.7, 105.1, 102.2, 60.8, 56.4, 56.0, 50.7, 42.4, 39.7, 34.3, 29.3, 20.5, 16.4. HRMS (ESI) m/z calc’d for C₂₁H₂₅NO₆ [M+H]⁺ 388.1755, found: 388.1765 (2.6 ppm).

• Methyl 3a-benzyl-10,11-dimethoxy-2-oxo-3,3a,7,8-tetrahydro-2H-furo[2′,3′:2,3]pyrrolo[2,1-a]isoquinoline-4-carboxylate (3c). Yield 0.083 g (64%), white solid, mp 218–220 °C. IR spectrum (KBr), υ/cm⁻¹: 1762, 1676 (C=O). ¹H NMR (600 MHz, CDCl₃) δ 7.07 (t, J = 7.6 Hz, 1H, H-Ph), 7.04 (s, 1H, 5-CH), 6.95 (t, J = 7.6 Hz, 2H, H-Ph), 6.71 (s, 1H, H-Ar), 6.59 (s, 1H, H-Ar), 6.25 (d, J = 7.6 Hz, 2H, H-Ph), 3.95 (s, 3H, OCH₃), 3.93 (s, 3H, OCH₃), 3.78 (s, 3H, OCH₃), 3.65 (d, J = 18.2 Hz, 1H, 3-CH₂), 3.46–3.42 (m, 1H, 7-CH₂), 3.31 (d, J = 14.1 Hz, 1H, -CH₂-Ph), 3.30–3.27 (m, 1H, 7-CH₂), 3.07 (d, J = 18.2 Hz, 1H, 3-CH₂), 2.65 (d, J = 14.1 Hz, 1H, -CH₂-Ph), 2.38–2.34 (m, 1H, 8-CH₂), 1.85–1.80 (m, 1H, 8-CH₂). ¹³C NMR (150 MHz, CDCl₃) δ 174.3, 165.1, 150.5, 148.6, 147.8, 135.6, 130.3, 130.2 (2C), 127.3 (2C), 126.5, 122.5, 111.5, 109.4, 104.7, 104.1, 58.0, 56.6, 56.3, 51.0, 42.3, 41.2, 39.3, 28.9. HRMS (ESI) m/z calc’d for C₂₅H₂₅NO₆ [M+H]⁺ 436.1755, found: 436.1757 (0.5 ppm).

• Methyl 10,11-dimethoxy-2-oxo-3a-phenyl-3,3a,7,8-tetrahydro-2H-furo[2′,3′:2,3]pyrrolo[2,1-a]isoquinoline-4-carboxylate (3d). Yield 0.077 g (61%), white solid, mp 212–214 °C. IR spectrum (KBr), υ/cm⁻¹: 1759, 1679 (C=O). ¹H NMR (600 MHz, CDCl₃) δ 7.37 (s, 1H, 5-CH), 7.10–7.08 (m, 2H, H-Ph), 7.06–7.04 (m, 1H, H-Ph), 7.02 (d, J = 7.6 Hz, 2H, H-Ph), 6.53 (s, 1H, H-Ar), 6.14 (s, 1H, H-Ar), 3.85–3.81 (m, 1H, 7-CH₂), 3.79 (s, 3H, OCH₃), 3.78 (br. D, J = 5.0 Hz, 2H, 3-CH₂), 3.75–3.73 (m, 1H, 7-CH₂), 3.57 (s, 3H, OCH₃), 3.54 (s, 3H, OCH₃), 3.04–3.00 (m, 1H, 8-CH₂), 2.82–2.79 (m, 1H, 8-CH₂). ¹³C NMR (150 MHz, CDCl₃) δ 174.1, 164.1, 149.6, 147.7, 146.9, 138.7, 128.3 (3C), 127.5, 126.4 (2C), 122.7, 110.9, 110.6, 109.4, 106.1, 60.8, 56.0, 55.9, 50.8, 42.4, 38.0, 29.1. HRMS (ESI) m/z calc’d for C₂₄H₂₃NO₆ [M+H]⁺ 422.1598, found: 422.1604 (1.4 ppm).

• Methyl 10,11-dimethoxy-3a-(4-methoxyphenyl)-2-oxo-3,3a,7,8-tetrahydro-2H-furo[2′,3′:2,3]pyrrolo[2,1-a]isoquinoline-4-carboxylate (3e). Yield 0.067 g (50%), light yellow solid, mp 196–198 °C. IR spectrum (KBr), υ/cm⁻¹: 1760, 1675 (C=O). ¹H NMR (600 MHz, CDCl₃) δ 7.34 (s, 1H, 5-CH), 6.92 (d, J = 8.6 Hz, 2H, H-Ar), 6.62 (d, J = 8.6 Hz, 2H, H-Ar), 6.53 (s, 1H, H-Ar), 6.18 (s, 1H, H-Ar), 3.84–3.80 (m, 1H, 7-CH₂), 3.81 (s, 3H, OCH₃), 3.75 (br. S, 2H, 3-CH₂), 3.73-3.71 (m, 1H, 7-CH₂), 3.69 (s, 3H, OCH₃), 3.58 (s, 6H, 2*OCH₃), 3.03–2.98 (m, 1H, 8-CH₂), 2.81–2.78 (m, 1H, 8-CH₂). ¹³C NMR (150 MHz, CDCl₃) δ 174.3, 164.2, 158.6, 149.6, 147.7, 146.6, 130.7, 128.3, 127.5 (2C), 122.7, 113.6 (2C), 110.9, 110.6, 109.4, 105.9, 60.4, 56.0, 55.9, 55.2, 50.8, 42.4, 38.2, 29.1. HRMS (ESI) m/z calc’d for C₂₅H₂₅NO₇ [M+H]⁺ 452.1704, found: 452.1714 (2.2 ppm).

• Methyl 3ª-(4-fluorophenyl)-10,11-dimethoxy-2-oxo-3,3ª,7,8-tetrahydro-2H-furo[2′,3′:2,3]pyrrolo[2,1-a]isoquinoline-4-carboxylate (3f). Yield 0.080 g (61%), white solid, mp 206–208 °C. IR spectrum (KBr), υ/cm⁻¹: 1771, 1683 (C=O). ¹H NMR (600 MHz, CDCl₃) δ 7.35 (s, 1H, 5-CH), 6.99–6.97 (m, 2H, H-Ar), 6.80–6.77 (m, 2H, H-Ar), 6.54 (s, 1H, H-Ar), 6.14 (s, 1H, H-Ar), 3.83–3.80 (m, 1H, 7-CH₂), 3.81 (s, 3H, OCH₃), 3.76 (d, J = 15.7 Hz, 2H, 3-CH₂), 3.75–3.71 (m, 1H, 7-CH₂), 3.58 (s, 6H, 2*OCH₃), 3.03–2.98 (m, 1H, 8-CH₂), 2.82–2.79 (m, 1H, 8-CH₂). ¹³C NMR (150 MHz, CDCl₃) δ 173.8, 164.1, 161.8 (d, J = 247.1 Hz, 1C), 149.7, 147.9, 146.9, 134.6, 128.4, 128.1 (d, J = 8.1 Hz, 2C), 122.4, 115.2 (d, J = 21.6 Hz, 2C), 111.0, 110.4, 109.3, 105.8, 60.4, 56.0, 55.9, 50.8, 42.4, 38.2, 29.1. HRMS (ESI) m/z calc’d for C₂₄H₂₂FNO₆ [M+H]⁺ 440.1504, found: 440.1500 (−0.9 ppm).

• Methyl 10,11-dimethoxy-3ª-(4-nitrophenyl)-2-oxo-3,3ª,7,8-tetrahydro-2H-furo[2′,3′:2,3]pyrrolo[2,1-a]isoquinoline-4-carboxylate (3g). Yield 0.018 g (13%), yellow solid, mp 147–149 °C. IR spectrum (KBr), υ/cm⁻¹: 1774, 1682 (C=O), 1519, 1347 (NO₂). ¹H NMR (600 MHz, CDCl₃) δ 7.98 (d, J = 8.8 Hz, 2H, H-Ar), 7.43 (s, 1H, 5-CH), 7.22 (d, J = 8.8 Hz, 2H, H-Ar), 6.58 (s, 1H, H-Ar), 6.12 (s, 1H, H-Ar), 3.90–3.83 (m, 3H, 3-CH₂, 7-CH₂), 3.81 (s, 3H, OCH₃), 3.78 (d, J = 17.4 Hz, 1H, 3-CH₂), 3.58 (s, 3H, OCH₃), 3.56 (s, 3H, OCH₃), 3.09–3.04 (m, 1H, 8-CH₂), 2.89–2.85 (m, 1H, 8-CH₂). ¹³C NMR (150 MHz, CDCl₃) δ 172.8, 163.7, 150.4, 148.1, 147.2, 147.0, 146.1, 128.8, 127.5 (2C), 123.5 (2C), 121.6, 111.3 (2C), 108.8 (2C), 60.8, 56.1, 56.0, 51.1, 42.5, 38.0, 29.0. HRMS (ESI) m/z calc’d for C₂₄H₂₂N₂O₈ [M+H]⁺ 467.1449, found: 467.1455 (1.3 ppm).

• Dimethyl 11-hydroxy-8,9-dimethoxy-11-(4-methoxyphenyl)-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepine-1,2-dicarboxylate (5a). Yield 0.079 g (55%), orange oil. IR spectrum (KBr), υ/cm⁻¹: 3521 (OH), 1723, 1709 (C=O). ¹H NMR (600 MHz, CDCl₃) δ 7.61 (s, 1H, 3-CH), 7.17 (s, 1H, 10-CH), 6.98 (d, J = 8.9 Hz, 2H, H-Ar), 6.77 (d, J = 8.9 Hz, 2H, H-Ar), 6.60 (s, 1H, 7-CH), 4.03–3.99 (m, 1H, 5-CH₂), 3.93 (s, 3H, OCH₃), 3.90 (s, 3H, OCH₃), 3.89 (s, 3H, OCH₃), 3.88–3.84 (m, 1H, 5-CH₂), 3.80 (s, 3H, OCH₃), 3.76 (s, 3H, OCH₃), 3.64 (s, 1H, OH), 2.98–2.94 (m, 1H, 6-CH₂), 2.86–2.82 (m, 1H, 6-CH₂). ¹³C NMR (150 MHz, CDCl₃) δ 169.6, 164.1, 159.6, 148.3, 147.6, 138.5, 137.2, 134.0, 128.4 (2C), 127.4, 127.2, 116.9, 114.0 (2C), 113.4, 113.3, 110.7, 77.7, 56.2, 56.1, 55.4, 52.8, 51.6, 48.2, 33.2. HRMS (ESI) m/z calc’d for C₂₆H₂₇NO₈ [M+Na]⁺ 504.1629, found: 504.1641 (2.4 ppm).

• Dimethyl 11-(4-fluorophenyl)-11-hydroxy-8,9-dimethoxy-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepine-1,2-dicarboxylate (5b). Yield 0.062 g (44%), orange oil. IR spectrum (KBr), υ/cm⁻¹: 3449 (OH), 1715 (C=O). ¹H NMR (600 MHz, CDCl₃) δ 7.59 (s, 1H, 3-CH), 7.17 (s, 1H, 10-CH), 7.06–7.03 (m, 2H, H-Ar), 6.94–6.91 (m, 2H, H-Ar), 6.61 (s, 1H, 7-CH), 4.02–3.98 (m, 1H, 5-CH₂), 3.93 (s, 3H, OCH₃), 3.90 (s, 3H, OCH₃), 3.89 (s, 3H, OCH₃), 3.87–3.85 (m, 1H, 5-CH₂), 3.80 (s, 3H, OCH₃), 3.75 (s, 1H, OH), 2.95–2.91 (m, 1H, 6-CH₂), 2.87–2.83 (m, 1H, 6-CH₂). ¹³C NMR (150 MHz, CDCl₃) δ 169.6, 164.0, 162.6 (d, J = 248.5 Hz, 1C), 148.5, 147.7, 142.2, 136.9, 133.7, 129.1 (d, J = 8.1 Hz, 2C), 127.5, 127.4, 117.0, 115.6 (d, J = 21.6 Hz, 2C), 113.6, 113.4, 110.6, 77.6, 56.2, 56.1, 52.9, 51.6, 48.4, 33.2. HRMS (ESI) m/z calc’d for C₂₅H₂₄FNO₇ [M+Na]⁺ 492.1429, found: 492.1434 (1.0 ppm).

• Methyl (1E)-8,9-dimethoxy-1-(2-methoxy-2-oxoethylidene)-10b-(4-methoxyphenyl)-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (6a). Yield 0.021 g (15%), beige solid, mp 227–229 °C. IR spectrum (KBr), υ/cm⁻¹: 1721, 1679 (C=O). ¹H NMR (600 MHz, CDCl₃) δ 7.31 (s, 1H, 3-CH), 7.21 (d, J = 8.8 Hz, 2H, H-Ar), 6.84 (d, J = 8.8 Hz, 2H, H-Ar), 6.60 (s, 1H, H-Ar), 6.42 (s, 1H, H-Ar), 5.60 (s, 1H, =CH-CO₂Me), 3.90 (s, 3H, OCH₃), 3.82 (s, 3H, OCH₃), 3.79 (s, 3H, OCH₃), 3.75 (s, 3H, OCH₃), 3.74–3.70 (m, 1H, 5-CH₂), 3.69 (s, 3H, OCH₃), 3.33–3.30 (m, 1H, 5-CH₂), 3.12–3.08 (m, 1H, 6-CH₂), 2.69–2.66 (m, 1H, 6-CH₂). ¹³C NMR (150 MHz, CDCl₃) δ 169.5, 165.7, 159.5, 148.4, 148.3, 146.8, 136.9, 130.6, 129.8 (2C), 129.3, 126.3, 120.0, 113.7 (2C), 111.4, 109.3, 94.4, 64.7, 56.2, 56.1, 55.4, 52.4, 51.0, 48.0, 28.8. HRMS (ESI) m/z calc’d for C₂₆H₂₇NO₇ [M+H]⁺ 466.1860, found: 466.1861 (0.2 ppm).

• Methyl (1E)-8,9-dimethoxy-1-(2-methoxy-2-oxoethylidene)-10b-(4-nitrophenyl)-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinoline-2-carboxylate (6b). Yield 0.045 g (31%), orange oil. IR spectrum (KBr), υ/cm⁻¹: 1733, 1699 (C=O), 1518, 1349 (NO₂). ¹H NMR (600 MHz, CDCl₃) δ 8.19–8.17 (m, 2H, H-Ar), 7.51–7.49 (m, 2H, H-Ar), 7.32 (s, 1H, 3-CH), 6.65 (s, 1H, H-Ar), 6.35 (s, 1H, H-Ar), 5.59 (s, 1H, =CH-CO₂Me), 3.91 (s, 3H, OCH₃), 3.83 (s, 3H, OCH₃), 3.75 (s, 3H, OCH₃), 3.71 (s, 3H, OCH₃), 3.68–3.64 (m, 1H, 5-CH₂), 3.41–3.39 (m, 1H, 5-CH₂), 3.16–3.11 (m, 1H, 6-CH₂), 2.73–2.70 (m, 1H, 6-CH₂). ¹³C NMR (150 MHz, CDCl₃) δ 169.0, 165.3, 150.2, 148.9, 148.7, 147.6, 146.8, 130.7, 129.3 (2C), 129.1, 126.4, 123.8 (2C), 118.8, 111.7, 109.0, 95.9, 64.6, 56.3, 56.1, 52.6, 51.2, 48.2, 28.5. HRMS (ESI) m/z calc’d for C₂₅H₂₄N₂O₈ [M+H]⁺ 481.1605, found: 481.1605 (0.0 ppm).

4. Conclusions

In summary, we have described a novel procedure for the synthesis of lactonic pyrrolo[2,1-a]isoquinolines and pyrido[2,1-a]isoquinolines through the rearrangements of 1-R-1-ethynyl-2-vinyl-1,2,3,4-tetrahydroisoquinolines in fluorinated alcohols. It has been demonstrated that the rearrangements depend on the acidity of the solvents used. In some cases, the addition of 3 equiv of AcOH increased the yields of the target lactones. The substituent at C-1 in the starting isoquinolines affects the composition and the ratio of the products in the transformation occurring in HFIP both with and without AcOH.