Aromatization of IMDAF adducts in aqueous alkaline media

Abstract

In this paper, we propose a simple synthesis of isoindoline-4-carboxylic acids by means of the aromatization of 3a,6-epoxyisoindoles in alkaline media. The method is facile from an experimental point of view: a short-term (0.5–2h) reflux of epoxyisoindoles in 5% aqueous solutions of alkali leads to the target products in 40–90% yields. The absence of by-products, ease of isolation of the target products and applicability to acidophobic group bearing substrates favorably distinguishes the proposed procedure from previously utilized acid-catalyzed methods. The proposed strategy has been successfully utilized for isoindole containing compounds and nuevamine-type alkaloids.

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Introduction

Isoindole chemistry is a thriving and relatively new area of organic chemistry; nevertheless, numerous synthetic approaches toward isoindoles have been proposed in the literature.¹ This advance is due to the large amount of biologically active isoindole-containing compounds found in nature² (for example, lennoxamine, aristoyagonine, nuevamine, chilenine and some other alkaloids).

Of all the isoindole fragment construction methods, the one that has attracted the most attention of our group over the last decade³ is a two-step approach based on the IMDAF (intramolecular Diels–Alder reaction of furans)⁴ reaction. The advantages of the method are cheap starting materials, wide chemical diversity (substituted furfurals can be used as the starting materials and various alkenyl halides, anhydrides and chlorides of α,β-unsaturated acids can be used in the acylation step) and the simplicity of the experimental procedure.

We have been trying to apply this approach for syntheses of isoindole-containing alkaloids and alkaloid-like compounds, particularly nuevamine and its derivatives (Fig. 1). We encountered problems in the final step of the route for our model compounds (see Results and discussion): aromatization of the 7-oxabicyclo[2.2.1]heptene fragment to 10,12a-epoxyisoindolo[1,2-a]isoquinoline using acid catalysis and common procedures was not successful.

Fig. 1 Proposed synthesis of nuevamine via the IMDAF reaction

The IMDAF approach towards isoindolines (Fig. 2) was suggested for the first time by Yugoslav (now Croatian) chemists in 1964.⁵ The authors proposed a number of reagents to be utilized in the final step as dehydrating agents: HBr/AcOH, H₂SO₄/AcOH and diluted H₂SO₄. This approach turned out to be so effective that it is still being widely used⁶ and improved.⁷ Thereupon, the method was extended to aromatization of the 3a,6-epoxy-2-benzofuran core.⁸

Fig. 2 The key step-aromatization of 3a,6-epoxyisoindole fragment

In addition to the above-mentioned reagents, H₃PO₄,³ HCl,^6ap-TSA^6g,7a and BF₃·OEt₂⁹ are also effective tools for this transformation. Two more methods⁷ of aromatization of 3a,6-epoxyisoindoles have been proposed: a protic ionic liquid based approach^7b (CF₃SO₃H/ionic liquid/microwave irradiation), and a method utilizing the K₁₀-Fe³⁺ catalyst coated on montmorillonite clay.^7c

Most of the mentioned conditions lead to good yields of the target isoindoles. However, all cited methods involve acid catalysis. It should be noted that proton or Lewis acids can produce unpredictable but often very interesting side transformations of the 7-oxabicyclo[2.2.1]heptene fragment.^5f,6e,9 See for example, the unexpected rearrangement of 2,3,7,7a-tetrahydro-3a,6-epoxyisoindol-1-ones to furo[2,3-c]pyrrolo[3,4-b]pyrrole-2,4,6-triones in 85% H₃PO₄.⁹ Another limitation of the described methods is their nonapplicability to the synthesis of isoindoles bearing acidophobic substituents (furyl, allyl, pyrrolyl, etc.)

There are a few studies on the aromatization of the 7-oxabicyclo[2.2.1]heptene moiety in strong alkaline media. As an illustration, a very limited number of publications on the aromatization of similar systems with metal–organic compounds and alcoholates can be mentioned.^8a,10 Dehydrative aromatization of 3-oxo-1,3-dihydro-2-benzofuran-4-carboxylic acids takes place in a 3M NaOMe solution^8a and aromatization of 7-oxabicyclo[2.2.1]heptanes can be carried out using t-BuLi.^10a Aromatization of epoxyisoindolyl phosphonates^10b can be performed in different conditions (H₃PO₄, TFA), but NaOMe/MeOH leads to several by-products.

We present a newly developed effective procedure of aromatization of 3a,6-epoxyisoindoles in 5% alkali aqueous solution, which was successfully utilized for the synthesis of nuevamine derivatives. To the best of our knowledge, this is the first time dilute aqueous alkaline solutions have been used as reaction media for this transformation. The approach allows the use of the Diels–Alder adducts of furan for the synthesis of diverse heterocycles annelated with a benzene ring, including ones bearing acidophobic fragments.

Results and discussion

The starting materials, exo-1-oxo-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-7-carboxylic acids 2a–l, were easily prepared from the commercially available amines and furfural in two steps (Scheme 1).

Scheme 1 Synthesis of the prerequisite 3,6a-epoxyisoindoles.

The reaction was performed according to the typical procedure.^3d,7a Furfurylamines 1a–l were purified by vacuum distillation and the target adducts 2a–l were obtained in a total yield of 40–65% (overall yield relative to furfural).

In order to study reactivity of the synthesized lactams, we tried to carry out the hydrolysis of the amide fragment of 2a in aqueous alkaline media. To our surprise, treatment of adduct 2a with a 10% aqueous solution of sodium hydroxide did not lead to 1-(aminomethyl)-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid (Scheme 2).

Scheme 2 Aromatization of 3a,6-epoxyisoindole-7-carboxylic acids 2a–l in alkaline medium.

Instead, 3-oxoisoindoline-4-carboxylic acid 3a was obtained as a single product in good yield. Then we optimized the experimental conditions to achieve maximum yields of the acids, 3, (Table 1) with the intention of developing a robust method of aromatization of 3a,6-epoxyisoindoles in aqueous alkaline media, which could be used as an alternative to the methods involving acidic conditions (Scheme 1).

Table 1 Dependence of isoindole yields on the reaction conditions

Comp.	Base	Conc. (%)	Solvent	Time (h)	Yield (%)
					before	after^a
					recrystallization
a Recrystallization from an i-PrOH/DMF mixture.
3a	NH3	25	H2O	2	0	0
3a	NaOH	2	H2O	2	0	0
3a	NaOH	5	H2O	0.5	92	52
3a	NaOH	5	H2O	1	86	53
3a	NaOH	5	H2O	2	70	49
3a	NaOH	10	H2O	1.5	67	50
3a	NaOH	5	EtOH	0.5	90	43
3b	NaOH	5	EtOH	2	83	45
3b	NaOH	5	MeOH	2	0	0
3b	NaOH	10	H2O	2	75	41
3b	NaOH	10	EtOH	1	89	46
3b	NaOH	15	EtOH	1	82	63

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The most accessible epoxides 2a,b were used as model substrates to optimize the yield. The reaction does not take place in 2–3% alkali (water or EtOH solutions) or a concentrated solution of ammonia (Table 1). The best results were obtained with 5–10% alkali solutions in water or ethanol (the yields are comparable). Reflux duration depends slightly on the structure of the initial substrate (the starting acid must be completely dissolved) and does not exceed 1.5 h. Apparently, the reaction temperature is required to be higher than 70 °C, since aromatization did not take place when the mixture was refluxed in a 5% NaOH methanol solution. Thus, for all further syntheses (see Scheme 2 and Table 2), we used a 10% solution of NaOH in water, with a 1.5 h reflux time.

Table 2 Yields and some characteristics of isoindole carboxylic acids 3a–l, 6a,b, 8a,b

Compound^a	R	Empirical formula	Found (%)			m.p. (°C)^b	IR (KBr)	Yield^b (%)
			Calculated (%)				ν (cm^−1)
			C	H	N		CO2H/NCO
a All compounds were obtained under the following conditions: a solution of NaOH (2.2 g, 56 mmol) and 1 g (3 mmol) of 2, 5 or 7 in 20 mL of water was refluxed for 1.5 h. See the Experimental section for the work-up procedure. b Yields and melting points of all compounds are given after recrystallization from i-PrOH/DMF. c Yields of the individual diastereoisomers of 8 are given after fractional crystallization, the total yields of 8a and 8b are given in the Experimental section.
3a	Ph	C15H11NO3	71.32	4.54	5.71	228.9–229.6	1714/1610	49
			71.14	4.38	5.53
3b	Bn	C16H13NO3	71.71	4.87	5.54	183–185	1713/1600	43
			71.90	4.90	5.24
3c	Me	C10H9NO3	62.42	4.34	7.15	207.6–210.9	1704/1609	65
			62.82	4.74	7.33
3d	Et	C11H11NO3	64.78	5.21	6.56	195.9–196.7	1712/1608	60
			64.38	5.40	6.83
3e	Allyl	C12H11NO3	66.65	5.31	6.75	166.7–168.2	1710/1608	45
			66.35	5.10	6.45
3f	Furfuryl	C14H11NO4	65.27	4.11	5.74	231.6–234.8	1706/1590	53
			65.37	4.31	5.44
3g	–(CH2)4CH3	C14H17NO3	68.34	6.72	5.36	144.4–144.9	1711/1609	47
			68.00	6.93	5.66
3h	–CH2C6H3Cl2-2,3	C16H11Cl2NO3	57.41	3.16	4.51	223–226	1704/1605	35
			57.16	3.30	4.17
3i	(CH2)2C6H3(OMe)2-3,4	C19H19NO5	66.65	5.81	4.41	193–194	1705/1605	48
			66.85	5.61	4.10
3j	3-Cl,4-Me-C6H3	C16H12ClNO3	63.39	4.22	4.85	259–262	1719/1597	30
			63.69	4.01	4.64
3k	Cyclohexyl	C15H17NO3	69.26	6.98	5.12	245–247	1703/1590	46
			69.48	6.61	5.40
3l	5-Methyl-1,2-oxazol-3-yl	C13H10N2O4	60.35	3.84	11.05	271.8–272.5	1726/1634	38
			60.47	3.90	10.85
6a	H	C17H13NO3	73.31	4.52	5.24	194–195 (decomp.)	1716/1610	60
			73.11	4.69	5.02
6b	OMe	C19H17NO5	67.33	5.20	4.30	160–161 (decomp.)	1732/1615	55
			67.25	5.05	4.13
8aA	—	C19H15NO4	70.10	4.76	5.03	236–238	1705/1620	7^c
			71.02	4.71	4.36
8aB	—	C19H15NO4	70.91	4.50	4.70	215–217	1722/1625	56^c
			71.02	4.71	4.36
8bA	—	C20H17NO4	71.58	5.39	4.49	259.6–260.6	1706/1623	14^c
			71.63	5.11	4.18
8bB	—	C20H17NO4	71.52	5.43	4.30	235–237	1713/1622	27^c
			71.63	5.11	4.18

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The exceptional ease of isolating the final products, 3, should be stressed. No extraction with organic solvents or column chromatography purification is required. After neutralization (diluted H₂SO₄) pure (according NMR ¹H data) target products 3 are separated by simple filtration and the only by-product is sodium sulfate.

Even after recrystallization (which in general leads to a 20–30% loss in yield—see Table 1) the yields of isoindolinecarboxylic acids 3 (Table 2) are comparable to those described in the literature.^{3d,5,7a,7b,10b} Recrystallization was performed in all cases in order to obtain analytically pure samples.

With the alkaline aromatization methodology developed for simple model systems, we proceeded to more complicated structures. The leitmotif of the further study was the investigation of the scope and limitations of the method applied to 3a,6-epoxyisoindoles condensed with other heterocycles (Schemes 3 and 4). A large number of such structures are described in the literature.^3,4

Scheme 3 Test synthesis of the Nuevamine-like systems.

Scheme 4 Observed epimerization in the course of alkaline aromatization.

The advantage of the procedure can be illustrated by the aromatization of the model nuevamine-like structures 5¹¹ containing the isoindolo[1,2-a]isoquinoline skeleton (Scheme 3 and Table 2). A comparison of acidic and basic reaction conditions for the synthesis of 6 shows that the latter lead to significantly higher yields of 6 and, apparently, may be successfully used in total synthesis of nuevamine.

The alkaline medium may lead to epimerization of the final products (Scheme 4 and Table 2). Aromatization of furo- or pyrano[3,2-c]-annelated 6b,9-epoxyisoindolo[1,2-a]quinolines 7¹² in basic conditions leads to a mixture of diastereomers 8A/8B, while the epimerization was not observed in the acidic conditions. In an independent experiment it was established that the isomerization of 8A to 8B occurs in the same conditions. The 8A/8B ratio in the formed mixtures is approximately the same.

Conclusions

We present an experimentally facile two-step method for the synthesis of isoindolone derivatives, which is based on the cleavage of IMDAF adducts in alkaline media. The availability of starting materials, mild conditions, benign reaction media and simple isolation procedure involving simple filtration make this approach very attractive. The method is a more robust alternative to the commonly used aromatization procedures in acidic conditions. Also, it makes previously inaccessible isoindoles bearing acidophobic substituents available and is preferential in cases leading to undesirable rearrangements under acidic conditions. We demonstrated the advantage of the developed aqueous alkaline medium procedure over the commonly used acidic conditions methods by the synthesis of nuevamine-like systems.

Experimental

All reagents were purchased from Acros Chemical Co. All solvents were used without further purification. Melting points were determined using a SMP30 and are corrected. IR spectra were obtained in KBr pellets for solids using an IR-Fourier spectrometer Infralum FT-801. NMR spectra ¹H (400 or 600 MHz) and ¹³C (100.6 or 150.9 MHz) were recorded for solutions in deuteriochloroform or DMSO-d₆ at 27 °C and traces of chloroform (¹H NMR δ 7.26 ppm and ¹³C NMR 76.90 ppm) or DMSO-d₅H (¹H NMR δ 2.49 ppm and ¹³C NMR 39.43 ppm) were used as the internal standard. Mass spectra were measured either on Thermo Trace DSQ (electron ionization, 70 eV, ion source temperature was 200 °C, direct inlet probe) or on JEOL AccuTOF JMS-T100LP spectrometer using direct analysis in real time (DART) ionization method (helium was used as DART gas, gas flow rate was 1 L min⁻¹, flow T 300 °C, discharge electrode was set to +4000 V, the mass scale was calibrated using PEG 600). The purity of the obtained substances and the composition of the reaction mixtures were controlled by TLC Sorbfile plates (using an EtOH/AcOH mixture as eluent). The separation of the final products was carried out by the crystallization from i-PrOH/DMF. Microanalysis was performed for C, H, N on a Vario Macro Cube C,H,N,O,S-analyser and were within ± 0.35% of theoretical values.

Hexahydro-3a,6-epoxyisoindol-7-carboxylic acids 2; General Procedure

A mixture of maleic anhydride (9.8 g, 0.1 mol) and N-R-furfurylamine 1a–k (0.1 mol) in benzene (100 ml) was stirred at 25 °C for 24 h. The precipitate formed was filtered off, washed with benzene (50 mL), ether (50 mL) and dried at 85 °C to constant weight. Compounds 2a–l were obtained in the form of fine crystalline white powders, which did not require further purification (satisfactory results of elemental analysis and NMR spectra).

Representative characteristics of epoxydes 2a,2b (all other data for 2c–2l are given in the ESI†) (3aS*,6R*,7S*,7aR*)-1-Oxo-2-phenyl-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindol-7-carboxylic acid (2a)

Yield: 86%; m.p. 183.1–184.9 °C.

This compound was obtained and described previously^3d,5b [lit.^3d: 184–185.5 °C, yield 86%; lit.^5b: 184–185 °C, yield 96%].

¹³C NMR (100.6 MHz, DMSO-d₆): δ = 45.4 (C_7a), 49.1 (C₃), 51.4 (C₇), 81.3 (C₆), 87.2 (C_3a), 119.3 (C_2′ and C_6′), 123.8 (C_4′), 128.5 (C_3′ and C_5′), 135.2 and 136.8 (C₅ and C₄), 139.5 (C_1′), 170.2 and 172.6 (C₁ and CO₂H).

MS (EI, 70 eV): m/z (%) = 271 (19) [M]⁺, 253 (50), 226 (33), 172 (100), 128 (30), 115 (26), 104 (45), 80 (74), 53 (45), 43 (25).

Anal. Calcd for C₁₅H₁₃NO₄: C, 66.41; H, 4.83; N, 5.16. Found: C, 66.21; H, 4.62; N, 5.01.

(3aS*,6R*,7S*,7aR*)-2-Benzyl-1-oxo-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindol-7-carboxylic acid (2b). Yield: 90%; m.p. 170.3–171.8 °C.

This compound was obtained and described previously^3d,7a,7b [lit.^3d: 164 °C, yield 90%; lit.^7a: 150 °C, yield 95%; lit.^7b: 151–152 °C, yield 76%].

¹³C NMR (100.6 MHz, DMSO-d₆): δ = 44.6 (C_7a), 45.3 and 47.6 (C₃ and C_CH2Ph), 50.2 (C₇), 81.1 (C₆), 88.4 (C_3a), 127.0 (C_4′), 127.4 and 128.5 (C_2′, C_3′, C_5′, C_6′), 135.7 and 136.6 (C₄ and C₅), 136.7 (C_1′), 170.6 and 172.9 (CO₂H and C₁).

Anal. Calcd for C₁₆H₁₅NO₄: C, C, 67.36; H, 5.30; N, 4.91. Found: C, 67.22; H, 5.11; N, 4.69.

3-Oxo-2-isoindoline-4-carboxylic acids 3; General Procedure. Epoxyisoindolinones 2a–l (3 mmol) were added to a 5–15% solution (15–25 mL) (see Table 2 and Table 1 footnote) of sodium hydroxide (tenfold molar excess approximately ∼1.2 g) in water or ethyl alcohol and heated under reflux for 0.5–2 h. The reaction mixture was cooled, poured into cold water (30 mL) and then a solution of sulphuric acid (∼20%) was added until it was slightly acidic. The formed precipitate was filtered off, washed with water (until neutral reaction of the rinsing water) and air-dried. Further recrystallization from a mixture of i-PrOH and DMF provided analytically pure acids 3a–l as white fine needle-shaped crystals.

Representative characteristics of isoindoles 3a,3b (all other data for 3c–l are given in the ESI†)

3-Oxo-2-phenylisoindoline-4-carboxylic acid (3a). This compound was obtained and described earlier^3d,5b,7a [lit.^3d: m.p. 227–230 °C, yield 46%; lit.^5b: m.p. 216–217 °C, yield 56%; lit.^7a: m.p. 164–165 °C, yield 55%].

¹³C NMR (100.6 MHz, DMSO-d₆): δ = 51.7 (C₁), 121.0 (C_2′ and C_6′), 125.5, 126.6, 128.6, 131.0, 132.2 (C₅, C₆, C₇, C_3′, C_4′, C_5′), 128.8 and 129.0 (C_3a and C₄), 137.4 (C_1′), 142.2 (C_7a), 164.5 and 167.7 (C₃ and CO₂H).

2-Benzyl-3-oxoisoindoline-4-carboxylic acid (3b). This compound was obtained and described earlier^3d,7b [lit.^3d: m.p. 177–178.5 °C, yield 33%; lit.^7b: m.p. 164–165 °C, yield 96%].

¹³C NMR (100.6 MHz, DMSO-d₆): δ = 46.4 (CH₂Ph), 50.8 (C₁), 127.7 (C_4′), 128.0 (C_2′ and C_6′), 128.7 (C_3′ and C_5′), 128.4 and 128.8 (C_3a and C₄), 127.7, 131.7, 132.2 (C₅, C₆, C₇), 135.8 (C_1′), 143.0 (C_7a), 164.7 and 168.9 (C₃ and CO₂H).

(8aS*,9R*,10S*,12aR*,12bR*)-8-Oxo-5,8,8a,9,10,12b-hexahydro-6H-10,12a-epoxyisoindolo[1,2-a]isoquinoline-9-carboxylic acid (5a) and (8aS*,9R*,10S*,12aR*,12bR*)-2,3-dimethoxy-8-oxo-5,8,8a,9,10,12b-hexahydro-6H-10,12a-epoxyisoindolo[1,2-a]isoquinoline-9-carboxylic acid (5b) were synthesized earlier.¹¹

Tetrahydroisoindolo[1,2-a]isoquinoline-9-carboxylic acids 6; General methods.
Method A. A solution of carboxylic acid 5a or 5b (1 g, ∼3 mmol) in orthophosphoric acid (15 mL) was stirred at 80–85 °C for 50 min. After cooling to room temperature, the reaction mixture was poured into water (50 mL). The precipitate formed was filtered off, washed with water (until neutral reaction of rinsing water) and air dried. Further crystallization of crude products from i-PrOH/DMF provided pure compounds 6a,b, as white fine needle-shaped crystals.
Method B. Carboxylic acid 5 (3.6 mmol) was added to a stirred solution of NaOH (1.43 g, 36 mmol) in 15 mL H₂O. The reaction mixture was heated under reflux for 1.5 h in argon atmosphere. After cooling to room temperature the reaction mixture was adjusted to pH ∼2–3 with concentrated HCl. The formed precipitate was filtered off, washed with water (3 × 15 mL) and air dried. The crude product was crystallized from i-PrOH/DMF to obtain pure compounds 6a,b.
Method C. A heterogeneous mixture of carboxylic acid 5 (3.6 mmol), and p-TSA (1.9 g, 11 mmol) in toluene (30 mL) was stirred under reflux for 4 h. Then toluene was decanted off and the resulting dark brown, vitriform residue was dissolved in hot CHCl₃ (3 × 50 mL) (a considerable part of the substance did not dissolve). The combined organic phases were washed with H₂O (3 × 100 mL), then with brine (100 mL), dried over MgSO₄, and concentrated in vacuo to give a viscous brown oil, which was purified by column chromatography (EtOAc-CHCl₃) to give no identifiable products.

8-Oxo-5,6,8,12b-tetrahydroisoindolo[1,2-a]isoquinoline-9-carboxylic acid (6a). ¹H NMR (400 MHz, DMSO-d₆): δ = 2.90–3.06 (m, 2 H, H-5), 3.61 (ddd, ³J_5A,6A = 5.7, ³J_5B,6A = 10.8, ²J_6,6 = 13.2 Hz, 1 H, H-6A), 4.28 (ddd, ³J_5A,6B = 3.2, ³J_5B,6B = 5.7, ²J_6,6 = 13.2 Hz, 1 H, H-6B), 7.33–7.21 (m, 3 H, H-2, H-3, H-4), 7.42 (br.s, 1 H, H-12b), 7.89 (t, ³J_10,11 = ³J_11,12 = 7.6 Hz, 1 H, H-11), 8.01 (dd, ³J_1,2 = 7.8, ⁴J_1,3 = 2.2 Hz, 1 H, H-1), 8.10 (d, ³J_11,12 = 7.6 Hz, 1 H, H-12), 8.49 (d, ³J_10,11 = 7.6 Hz, 1 H, H-10), 15.12 (br.s, 1 H, CO₂H).

¹³C NMR (100.6 MHz, DMSO-d₆): δ = 28.7 (C₅), 35.0 (C₆), 86.5 (C_12b), 126.6, 127.8, 128.0, 129.1 (C₁, C₂, C₃, C₄), 127.2 (C₉), 128.8 (C_8a), 133.3 and 132.3 (C₁₀ and C₁₁), 128.4 (C₁₂), 136.1 and 134.4 (C_12c and C_4a), 149.2 (C_12a), 164.9 (C₈), 166.8 (CO₂H).

MS (EI, 70 eV): m/z (%) = 279 (25), 250 (21), 235 (100), 206 (29), 178 (39), 130 (16), 103 (24), 77 (39), 43 (40).

2,3-Dimethoxy-8-oxo-5,6,8,12b-tetrahydroisoindolo[1,2-a]isoquinoline-9-carboxylic acid (6b). ¹H NMR (400 MHz, DMSO-d₆): δ = 2.84–3.00 (m, 2 H, H-5), 3.59 (ddd, ³J_5A,6A = 5.0, ³J_5B,6A = 9.5, ²J_6,6 = 13.1 Hz, 1 H, H-6A), 3.73 (s, 3 H, OMe), 3.82 (s, 3 H, OMe), 4.29 (ddd, ³J_5A,6B = 3.6, ³J_5B,6B = 5.7, ²J_6,6 = 13.1 Hz, 1 H, H-6B), 7.45 (br.s, 1 H, H-12b), 6.78 (s, 1 H, H-4), 7.33 (s, 1 H, H-1), 7.88 (t, ³J_10,11 = ³J_11,12 = 7.6 Hz, 1 H, H-11), 8.09 (d, ³J_12,11 = 7.6 Hz, 1 H, H-12), 8.54 (d, ³J_10,11 = 7.6 Hz, 1 H, H-10), 15.65 (br.s, 1 H, CO₂H).

¹³C NMR (100.6 MHz, DMSO-d₆): δ = 28.6 (C₅), 35.1 (C₆), 55.5 and 56.0 (2 × OMe), 86.3 (C_12b), 111.1 and 111.8 (C₁ and C₄), 126.93, 126.96, 127.7, 128.8 (C_4a, C_8a, C₉, C_12c), 127.9, 132.1, 133.3 (C₁₀, C₁₁, C₁₂), 147.6, 149.0, 149.6 (C₂, C₃, C_12a), 164.9 and 166.9 (C₈ and CO₂H).

MS (EI, 70 eV): m/z (%) = 339 (100), 324 (46), 308 (50), 295 (95), 278 (34), 165 (43), 77 (50), 43 (69).

(3aR*,9aR*,10S*,11R*,13aS*,13bR*,13cR*)-9-Oxo-1,2,9,9a,10,11,13b,13c-octahydro-3aH-11,13a-epoxyfuro[3,2-c]isoindolo[2,1-a]quinoline-10-carboxylic acid (7a) and (4aR*,10aR*,11S*,12R*,14aS*,14bR*,14cR*)-10-oxo-2,3,10,10a,11,12,14b,14c-octahydro-1H,4aH-12,14a-epoxyisoindolo[2,1-a]pyrano[3,2-c]quinoline-11-carboxylic acid (7b) were synthesized earlier.¹²

Aromatization of acids 7; General methods.
Method A. A solution of carboxylic acid 7a or 7b (∼1 g, 2.8 mmol) in 15 mL H₃PO₄ was stirred at 85 °C for 30 min. After cooling to room temperature, the reaction mixture was poured into water (50 mL). The formed precipitate was filtered off and air-dried. Recrystallization from i-PrOH/DMF produced white needle-shaped crystals of 8 in the form of the single diastereoisomer 8aA, 8bA.
Method B. Carboxylic acid 7 (3.6 mmol) was added to a stirred solution of NaOH (1.44 g, 36 mmol) in H₂O (13 mL). The reaction mixture was heated under reflux for 1.5 h. After cooling to room temperature the reaction mixture was adjusted to pH 2–3 with concentrated HCl. The formed precipitate was filtered off, washed with water (2 × 15 mL) and air dried affording a mixture of diastereomers 8aA/8aB, 8bA/8bB. The isomer ratio (according to ¹H NMR) is given in Scheme 4. Multiple fractional crystallization of these mixtures from i-PrOH/DMF afforded pure compounds 8aA, 8aB and 8bA, 8bB as individual diastereoisomers.

(3aR*,13bR*,13cR*)-9-Oxo-1,2,3a,9,13b,13c-hexahydrofuro[3,2-c]isoindolo[2,1-a]quinoline-10-carboxylic acid (8aA), trans-isomer. This compound was obtained and described earlier by our group¹² [lit.¹²: 236–238 °C, yield 89%].

¹³C NMR (100.6 MHz, DMSO-d₆): δ = 23.9 (C₁), 39.1 (C_13c), 59.2 (C_13b), 65.8 (C₂), 74.1 (C_3a), 119.1 (C₇), 128.1, 129.4, 130.2, 133.7 (C_3b, C_7a, C_9a, C₁₀), 125.2, 125.8, 127.7, 129.7, 131.1, 132.5 (C₄, C₅, C₆, C₁₁, C₁₂, C₁₃), 144.4 (C_13a), 164.6 and 166.3 (C₉ and CO₂H).

(3aR*,13bS*,13cR*)-9-Oxo-1,2,3a,9,13b,13c-hexahydrofuro[3,2-c]isoindolo[2,1-a]quinoline-10-carboxylic acid (8aB), cis-isomer. ¹H NMR (600 MHz, DMSO-d₆): δ = 2.39 (m, 1 H, H-1B), 2.47 (m, 1 H, H-13c), 2.52 (m, 1 H, H-1A), 3.80 (m, 1 H, H-2B), 4.10 (m, 1 H, H-2A), 4.64 (d, ³J_13b,13c = 11.7 Hz, 1 H, H-13b), 4.68 (d, ³J_3a,13c = 5.5 Hz, 1 H, H-3a), 7.26 (t, ³J_4,5 = ³J_5,6 = 7.6 Hz, 1 H, H-5), 7.43 (ddd, ⁴J_4,6 = 1.4, ³J_5,6 = 7.6, ³J_6,7 = 8.2 Hz, 1 H, H-6), 7.52 (d, ³J_4,5 = 7.6 Hz, 1 H, H-4), 7.82 (t, ³J_11,12 = ³J_12,13 = 7.6 Hz, 1 H, H-12), 8.02 (d, ³J_12,13 = 7.6 Hz, 1 H, H-13), 8.04 (d, ³J_11,12 = 7.6 Hz, 1 H, H-11), 8.17 (d, ³J_6,7 = 8.2 Hz, 1 H, H-7).

¹³C NMR (100.6 MHz, DMSO-d₆): δ = 28.7 (C₁), 41.4 (C_13c), 58.6 (C_13b), 65.6 (C₂), 75.6 (C_3a), 120.2 (C₇), 126.6, 128.8, 130.1, 133.7 (C_3b, C_7a, C_9a, C₁₀), 125.2, 126.5, 128.6, 130.7, 131.0, 132.9 (C₄, C₅, C₆, C₁₁, C₁₂, C₁₃), 145.7 (C_13a), 165.63 and 165.60 (C₉ and CO₂H).

HRMS (DART) m/z (rel. intensity): 322.110 (2) [M+H]⁺ (100) (exact mass for C₁₉H₁₅NO₄ 321.1001), 323.12 (27).

Anal. Calcd for C₁₉H₁₅NO₄: C, 71.02; H, 4.71; N, 4.36. Found: C, 71.31; H, 4.54; N, 4.57.

(4aR*,14bR*,14cR*)-10-Oxo-2,3,4a,10,14b,14c-hexahydro-1H-isoindolo[2,1-a]pyrano[3,2-c]quinoline-11-carboxylic acid (8bA), trans-isomer. This compound was obtained and described earlier by our group¹² [lit.¹²: 260 °C, yield 77%].

¹³C NMR (100.6 MHz, DMSO-d₆): δ = 16.9 (C₂), 23.6 (C₁), 34.3 (C_14c), 59.9 (C₃), 61.6 (C_14b), 70.1 (C_4a), 119.1 (C₈), 125.1, 125.6, 127.0, 127.5, 131.1, 132.5 (C₅, C₆, C₇, C₁₂, C₁₃, C₁₄), 125.7, 128.8, 129.4, 134.8 (C_4b, C_8a, C_10a, C₁₁), 143.3 (C_14a), 164.6 and 166.1 (C₁₀ and CO₂H).

(4aR*,14bS*,14cR*)-10-Oxo-2,3,4a,10,14b,14c-hexahydro-1H-isoindolo[2,1-a]pyrano[3,2-c]quinoline-11-carboxylic acid (8bB), cis-isomer. ¹H NMR (600 MHz, DMSO-d₆): δ = 1.54 (m, 1 H, H-1B), 1.90 (m, 2 H, H-1A, H-2B), 2.03 (m, 1 H, H-2A), 2.29 (m, 1 H, H-14c), 3.74 (t, ²J_3A,3B = ³J_3B,2A = 11.0 Hz, 1 H, H-3B), 4.03 (dd, ³J_3B,2 = 4.1, ²J_3A,3B = 11.0 Hz, 1 H, H-3A), 4.56 (br.s, 1 H, H-4a), 5.35 (d, ³J_14b,14c = 11.0 Hz, 1 H, H-14b), 7.19 (t, ³J_5,6 = ³J_6,7 = 7.6 Hz, 1 H, H-6), 7.39 (dd, ³J_6,7 = 7.6, ³J_7,8 = 8.2 Hz, 1 H, H-7), 7.40 (d, ³J_5,6 = 7.6 Hz, 1 H, H-5), 7.83 (m, 2 H, H-12, H-14), 8.04 (dd, ³J_13,14 = 5.5, ³J_13,14 = 8.3 Hz, 1 H, H-13), 8.24 (d, ³J_7,8 = 8.2 Hz, 1 H, H-8).

¹³C NMR (100.6 MHz, DMSO-d₆): δ = 21.0 (C₂), 23.7 (C₁), 38.4 (C_14c), 57.1 (C_14b), 68.6 (C₃), 74.1 (C_4a), 119.7 (C₈), 125.1, 127.8, 129.0, 130.9, 131.2, 132.6 (C₅, C₆, C₇, C₁₂, C₁₃, C₁₄), 127.3, 129.1, 130.2, 134.5 (C_4b, C_8a, C_10a, C₁₁), 144.4 (C_14a), 165.6 and 167.1 (C₁₀ and CO₂H).

HRMS (DART) m/z (rel. intensity): 336.126 (3) [M+H]⁺ (100) (exact mass for C₂₀H₁₇NO₄ 335.1158), 337.13 (18).

Anal. Calcd for C₂₀H₁₇NO₄: C, 71.63; H, 5.11; N, 4.18. Found: C, 71.38; H, 5.50; N, 3.97.

Acknowledgements

This work was supported by the Russian Foundation for Basic Research (grant no. 07-03-00083a).

References

1. (a) For reviews on isoindole chemistry, see: T. J. Donohoe, In Science of Synthesis; E. J. Thomas Ed.; Georg Thieme Verlag; Stuttgart, 2000, Vol. 10, p. 653; (b) G. B. Jones and B. J. Chapman, In Comprehensive Heterocyclic Chemistry II, A. R. Katrizky, C. W. Rees, E. F. V. Scriven ed.; Pergamon: Oxford, 1996, Vol. 2, p. 1; (c) V. A. Kovtunenko and Z. V. Voitenko, Russ. Chem. Rev., 1994, 63, 997–1018; (d) R. Bonnett and S. A. North, Adv. Heterocycl. Chem., 1982, 29, 341; (e) F. S. Babichev, V. A. Kovtunenko and A. K. Tyltin, Russ. Chem. Rev., 1981, 50, 1087–1103; (f) J. D. White and M. E. Mann, Adv. Heterocycl. Chem., 1969, 10, 113.
2. (a) Reviews on methods of construction of the [1,2] isoindolo-condensed heterocycles: E. V. Boltukhina, F. I. Zubkov and A. V. Varlamov, Chem. Heterocycl. Compd., 2006, 42, 831–857; (b) E. V. Boltukhina, F. I. Zubkov and A. V. Varlamov, Chem. Heterocycl. Compd., 2006, 42, 971–1001.
3. (a) A. V. Varlamov, N. V. Sidorenko, F. I. Zubkov and A. I. Chernyshev, Chem. Heterocycl. Compd., 2002, 38, 490–491; (b) F. I. Zubkov, E. V. Boltukhina, K. F. Turchin and A. V. Varlamov, Tetrahedron, 2004, 60, 8455–8463; (c) V. V. Kouznetsov, F. I. Zubkov, U. M. Cruz, L. G. Voskressensky, L. Y. Vargas Mendez, L. Astudillo and E. E. Stashenko, Lett. Org. Chem., 2004, 1, 37–39; (d) A. V. Varlamov, E. V. Boltukhina, F. I. Zubkov, N. V. Sidorenko, A. I. Chernyshev and D. G. Grudinin, Chem. Heterocycl. Compd., 2004, 40, 22–28; (e) F. I. Zubkov, E. V. Boltukhina, K. F. Turchin, R. S. Borisov and A. V. Varlamov, Tetrahedron, 2005, 61, 4099–4113; (f) V. V. Kouznetsov, U. M. Cruz, F. I. Zubkov and E. V. Nikitina, Synthesis, 2007, 375–384.
4. (a) The latest reviews on IMDAF reactions: F. I. Zubkov, E. V. Nikitina and A. V. Varlamov, Russ. Chem. Rev., 2005, 74, 639–669; (b) P. Vogel, J. Cossy, J. Plumet and O. Arjona, Tetrahedron, 1999, 55, 13521–13642; (c) C. O. Kappe, S. S. Murphree and P. Albert, Tetrahedron, 1997, 53, 14179–14233; (d) G. Brieger and J. N. Bennett, Chem. Rev., 1980, 80, 63–97.
5. (a) D. Bilović, Ž. Stojanac and V. Hahn, Tetrahedron Lett., 1964, 2071–2074; (b) D. Bilović, Croat. Chem. Acta, 1966, 38, 293–298 ( Chem. Abstr. , 1967 , 66 , 55416 ); (c) D. Bilović and V. Hahn, Croat. Chem. Acta, 1967, 39, 189–197 ( Chem. Abstr. , 1968 , 68 , 105055 ); (d) D. Bilović, Croat. Chem. Acta, 1968, 40, 15–22 ( Chem. Abstr. , 1968 , 69 , 486751 ); (e) A. D. Mance, B. Borovička, B. Karaman and K. Jacopčić, J. Heterocycl. Chem., 1999, 36, 1337–1341; (f) A. D. Mance, B. Borovička, K. Jacopčić, G. Pavlović and I. Leban, J. Heterocycl. Chem., 2002, 39, 277–285.
6. (a) J. E. Hernández, S. Fernández and G. Arias, Synth. Commun., 1988, 18, 2055–2061; (b) D. Prajapati, D. R. Borthakur and J. S. Sandhu, J. Chem. Soc., Perkin Trans. 1, 1993, 1, 1197–1200; (c) L. Sader-Bakaouni, O. Charton, N. Kunesch and F. Tillequin, Tetrahedron, 1998, 54, 1773–1782; (d) R. Murali, H. Surya Prakash Rao and H. W. Scheeren, Tetrahedron, 2001, 57, 3165–3174; (e) A. Padwa, K. R. Crawford, C. S. Straub, S. N. Pieniazek and K. N. Houk, J. Org. Chem., 2006, 71, 5432–5439; (f) X. Huang and J. Xu, J. Org. Chem., 2009, 74, 8859–8861; (g) A. A. Mir, V. V. Mulwad and G. K. Trivedi, J. Heterocyclic Chem., 2010, 47, 214–218.
7. (a) P. S. Sarang, A. A. Yadav, P. S. Patil, U. M. Krishna, G. K. Trivedi and M. M. Salunkhe, Synthesis, 2007, 1091–1095; (b) C. P. Gordon, N. Byrne and A. McCluskey, Green Chem., 2010, 12, 1000–1006; (c) D. D. Claeys, C. V. Stevens, B. I. Roman, P. Van De Caveye, M. Waroquier and V. Van Speybroeck, Org. Biomol. Chem., 2010, 8, 3644–3654.
8. (a) A. Pelter and B. Singaram, J. Chem. Soc., Perkin Trans. 1, 1983, 1383–1386; (b) I. N. Namboothiri, M. Ganesh, S. M. Mobin and M. Cojocaru, J. Org. Chem., 2005, 70, 2235–2243.
9. A. Ilyin, V. Kysil, M. Krasavin, I. Kurashvili and A. V. Ivachtchenko, J. Org. Chem., 2006, 71, 9544–9547.
10. (a) A. Pelter and B. Singaram, Tetrahedron Lett., 1982, 23, 245–248; (b) G. O. Kachkovskyi and O. I. Kolodiazhnyi, Phosphorus, Sulfur Silicon Relat. Elem., 2009, 184, 890–907.
11. F. I. Zubkov, J. D. Ershova, A. A. Orlova, V. P. Zaytsev, E. V. Nikitina, A. S. Peregudov, A. V. Gurbanov, R. S. Borisov, V. N. Khrustalev, A. M. Maharramov and A. V. Varlamov, Tetrahedron, 2009, 65, 3789–3803.
12. (a) F. I. Zubkov, V. P. Zaitsev, A. M. Piskareva, M. N. Eliseeva, E. V. Nikitina, N. M. Mikhailova and A. V. Varlamov, Russ. J. Org. Chem., 2010, 46, 1192–1206; (b) F. I. Zubkov, V. P. Zaitsev, A. S. Peregudov, N. M. Mikhailova and A. V. Varlamov, Russ. Chem. Bull., 2007, 56, 1063–1079.

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Footnote

† Electronic Supplementary Information (ESI) available: full physicochemical and spectral data of all synthesized compounds. See DOI: 10.1039/c2ra20295f/

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