Highly diastereo- and enantioselective organocatalytic synthesis of new heterocyclic hybrids isoindolinone-imidate and isoindolinone-phthalide

Abstract

New heterocyclic hybrids were synthesized in an aldol initiated organocascade reaction of nucleophilic isoindolinones with 2-formyl benzonitriles (2-cyano benzaldehydes). Excellent diastereo- and enantioselectivities and good yields were obtained in the presence of bifunctional organocatalysts. In addition, a new application of the Staudinger reaction has been proposed for the synthesis of substituted nucleophilic isoindolinones.

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Introduction

Powerful strategies in drug discovery include the covalent combinations of different bioactive agents, directly bonded or spaced by a linker, useful to increase the therapeutic potential of the resulting hybrid molecules over single parent agents.¹ Recent examples of this concept comprise the synthesis of a series of new heterocycle hybrids, which actually show enhanced pharmacological properties.¹ However, to the best of our knowledge, synthetic routes to allow the access to combinations of isoindolinone and isobenzofuranone (phthalides) have never been reported, despite the broad range of biological activities shown by the two distinct classes.^2,3 The presence of a stereocenter in both isoindolinone and phthalide rings, might constitute a major challenge when designing covalently bonded hybrids, even though in the last years great attention has been addressed to the synthesis of chiral, non-racemic derivatives belonging to the single classes respectively.^4–7 As part of ongoing research efforts in the asymmetric synthesis of bioactive heterocycles, we are interested in such derivatives, aiming to combine two well-known pharmacophores in a single molecule. The development of this type of synthetic methodologies is of fundamental importance to achieve structural diversity and chemical novelty, a purpose to effectively tackle the major challenges in medicinal chemistry. Our previous studies demonstrated the effectiveness of an organocascade reactions of 2-formyl benzonitriles (2-cyano benzaldehydes) with a series of nucleophiles,⁶ a powerful approach also adopted by other groups^4e,f in the synthesis of bioactive 3-substituted isoindolinones and phthalides with very good yields and enantioselectivity. In addition, we also proposed the use of isoindolinones, activated in 3-position by an electron-withdrawing group, as nucleophiles in asymmetric Michael reactions for the construction of derivatives with tetrasubstituted stereocenters.⁷ This is an important topic poorly investigated in isoindolinone chemistry,^2,3,7,8 while it has been extensively studied in phthalide synthesis.^5e,f On the basis of these considerations, we envisioned new routes in designing novel heterocyclic hybrids, combining both the previous findings, namely by investigating the reactivity of the nucleophilic isoindolinones with electrophiles bearing two adjacent electrophilic groups. A supposed cascade aldol-cyclization pathway should drive the reaction towards the formation of the desired compounds with adjacent trisubstituted and tetrasubstituted stereocenters.

Results and discussion

The preliminary results about achiral versions of the proposed strategies were particularly encouraging. In presence of only K₂CO₃ in CH₃CN, 2-formyl methylbenzoate, as well as 2-formyl benzonitrile, gave the racemic hybrids in very good yields and good diastereoselectivity (>20/1), according to pathways A and B of Scheme 1.

Scheme 1 Alternative approaches to racemic isoindolinone–isobenzofuranone hybrids.

Both the imidate intermediate 5 and the final compound 3 were characterized by HRMS and NMR spectra, while we were not able to produce suitable single crystals for X-ray analysis. The ¹H-NMR spectra show an aromatic proton at unusually high-field (δ 5.63 and 5.79 for 5 and 3, respectively). The aromatic nature of that proton has been clearly demonstrated by a bidimensional COSY experiment (Fig. 1).

Fig. 1 COSY-NMR of 3.

This unusual value of chemical shift has simplified the determination of the relative configuration of 3 through the computation of the chemical shifts. Fig. 2 shows the comparison of the experimental chemical shifts with those computed after scaling⁹ at the SCRF-B3LYP/6-31+G**//B3LYP/6-31G* level using Gaussian.¹⁰ The best agreement between calculated and experimental chemical shift is obtained for the diastereomer SR-RS; the larger discrepancies for the SS model at 6.46 and 5.79 ppm refer to the N–H proton (a known difficult case for standard ab initio calculations¹¹), and to the aforementioned aromatic proton, whose chemical shift is instead well reproduced by the computations on the SR-RS model.

Fig. 2 Comparison of experimental chemical shifts with those computed at the SCRF-B3LYP/6-31+G**//B3LYP/6-31G* level.

The better agreement of computed spectra for the SR configuration is grossly unchanged by consideration of the lowest energy conformer out of the 18 used to compute the spectra (See ESI†). Fig. 3 shows these lowest energy conformers. It can be realized that a proton of 3-SR-1 actually lies within the shielding cone of a benzene ring. Interestingly, 3-SR-1 and 3-SS-1 are both characterized by a weak hydrogen-bonding between the isoindolinonic N–H and the ester oxygen (2.59 Å and 2.78 Å, respectively); however the structure of 3-SR-1 has a further weak hydrogen-bonding between the isoindolinonic N–H and the lactamic O atom (2.82 Å). Consistently, 3-SR-1 is favored over that of 3-SS-1 by 0.6 kcal mol⁻¹.

Fig. 3 Model of the lowest energy conformers of 3-SR and 3-SS. The aromatic proton lying inside the shielding cone of the aromatic ring of the isoindolinone subunit is highlighted in blue.

Once obtained and characterized the racemic derivatives, we investigated asymmetric versions of these reactions, focusing on both organocatalysts and phase transfer catalysts as the chiral ammonium salt 6 (Fig. 4), focusing on both pathway A and B of Scheme 1.

Fig. 4 Catalytic systems tested in asymmetric versions.

According to the first experiments (Table 1), cinchona-alkaloid based phase transfer catalysis was less effective than tertiary amine base organocatalysis (entries 1 and 3 vs. entries 2 and 4), while 2-formyl benzonitrile was more promising than 2-formyl methylbenzoate, giving a good er of 92/8 with high diastereoselectivity (dr > 20/1) and good yields in the presence of 10 mol% of 7 (entry 4). Despite the longer synthetic pathway, the use of 2-formyl benzonitrile has the additional advantage of allowing the access to another class of interesting heterocycles 5 with the imidate functionality,¹² which was then conveniently converted into the phthalide 3 by hydrolysis.

Table 1 Preliminary asymmetric investigation

Entry^a	Pathway (see Scheme 1)	Catalyst – (mol%)	t (h or d)	Yield^b	er^c
a Reaction conditions: rt, solvent DCM, [1] = 0.029 M.b Yields refer to isolated chromatographically pure compounds for one-step pathway A or two-step pathway B.c Determined by HPLC on chiral column.
1	A	6 (10%)/K2CO3 (1 eq.)	4 h	82	65/35
2	A	7 10%	7 d	23%	68/32
3	B	6 (10%)/K2CO3 (1 eq.)	4 h	74%	52/48
4	B	7 10%	24 h	84%	92/8

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The screening of conditions performed with catalyst 7 (pathway B, Table 2), led to the identification of xylene as the best solvent for this system, and after the optimization of medium concentration, a very good 95/5 er was obtained (entry 6). Luckily, the same trend was observed with the commercially available organocatalyst 8, a (1R,2R)-(−)-2-(dimethylamino)cyclohexyl]thiourea derivative, known as Takemoto's catalyst,¹³ leading to ent-3a with an excellent er of 97/3 (entry 8). Decreasing the catalyst loading at 5 mol%, comparable yield and selectivities were obtained in a slightly longer reaction time (entry 11). Thus, under the conditions of entry 8 in Table 2, the reaction was successfully scaled up to a 0.4 mmol scale with unchanged efficiency (entry 12).

Table 2 Optimization of reaction conditions of asymmetric version, pathway B

Entry	Solvent/[1]^a	Catalyst	t (h)	Yield^b (%)	er^c
a Reaction conditions: rt, solvent, [1] = M.b Yields refer to chromatographically pure compounds of the two-step sequence.c Determined by HPLC on chiral column.d Performed at 0 °C.e Catalysts used at 5 mol%.f Performed on 0.4 mmol scale.
1	DCM/[0.029]	7	24	87	92/8
2^d	DCM/[0.029]	7	24	84	90/10
3	Toluene/[0.029]	7	18	85	91/9
4	THF/[0.029]	7	—	—
5	p-Xylene/[0.029]	7	3	84	93/7
6	p-Xylene/[0.023]	7	4	87	95/5
7	p-Xylene/[0.019]	7	5	83	94/6
8	p-Xylene/[0.023]	8	3	86	3/97
9	p-Xylene/[0.019]	8	4.5	88	4/96
10	p-Xylene/[0.029]	8	1.5	87	4/96
11	p-Xylene/[0.029]	8^e	8	84	4/96
12^f	p-Xylene/[0.023]	8	4	84	4/96

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Then, the scope of the reaction was briefly investigated under the optimized conditions (Scheme 2). Excellent yields, diastereo- (>20/1) and enantioselectivities were observed in the presence of other 2-formyl benzonitriles¹⁴ substituted with halogens, with the electron-releasing methoxy and with additional aryl groups like phenyl and the very hindered α-naphthyl group, furnishing, in the latter cases, particularly complex motifs of chiral hybrid heterocycles linked to aromatic rings. Only in the presence of the strong electron-withdrawing group in 4-NO₂-2-cyanobenzaldehyde a significantly lower ee was observed. Comparable excellent results were obtained reacting the nucleophilic isoindolinone 1b, with a Br on the aromatic ring.

Scheme 2 Analysis of the scope.

Interestingly, 1b was synthesized modifying the reported route to unsubstituted 1a,¹⁵ introducing a Staudinger reaction¹⁶ in the last step for the reduction-lactamization reaction performed on the acyclic azide intermediate 10 (Scheme 3). In this case, the use of PMe₃ was crucial whereas PPh₃ and other reduction reactions failed. The intermediate 10 was conveniently synthesized, according to reported procedures,¹⁵ starting from homophthalic acid 9, which was subjected to bromination with KBrO₃ on the aromatic ring, followed by Fischer esterification, radical bromination at the benzylic position and substitution with NaN₃ (see ESI† for further details).

Scheme 3 Route to substituted nucleophilic isoindolinones 1.

Experimental part

For detailed experimental information, spectra and chromatograms of all the new compounds see the ESI.†

Procedures for the synthesis of 3-carboethoxy-isoindolinones 1a,b

Isoindolinone 1a was synthesized according to reported procedures as described in Scheme S1 (See ESI† for details).¹⁵ Isoindolinone 1b was obtained by a modification of the main route consisting of bromination of homophthalic acid with potassium bromated in sulfuric acid to give the brominated diacid, by Fischer esterification, radical bromination and reduction of the corresponding azide by Staudinger reaction.

Ethyl 5-bromo-3-oxoisoindoline-1-carboxylate 1b. To a solution of ethyl 2-((ethoxycarbonyl)azidomethyl)-5-bromobenzoate (70 mg, 0.197 mmol, 1 equiv.) in THF/H₂O (2 mL/200 μL) under nitrogen atmosphere, trimethylphosphine (1 M in THF, 235 μL, 1.2 equiv.) was added and the mixture was stirred for 16 h at room temperature. After evaporation of the solvent, the crude was taken up with dichloromethane and washed with water. Purification by chromatography (ethyl acetate 3/hexane 7) gave a white solid. Yield: 55%. Mp 163–165 °C. ¹H-NMR (300 MHz): 7.99 (s, 1H), 7.73 (d, 1H, J = 8.1 Hz), 7.60 (d, 1H, J = 8.1 Hz), 7.14 (bs, 1H, NH), 5.21 (s, 1H), 4.32–4.24 (m, 2H), 1.32 (t, 3H, J = 7.2 Hz). ¹³C-NMR (100 MHz): 170.6, 169.1, 140.7, 136.6, 134.5, 128.4, 126.5, 124.7, 63.8, 59.6, 15.3. HRMS (ESI): m/z calcd for C₁₁H₁₀BrNO₃ + H⁺: 283.99168, found 283.99168. Anal. calcd for C₁₁H₁₀BrNO₃: C, 46.50; H, 3.55; N, 4.93. Found: C, 46.53; H, 3.41; N, 5.04.

Procedures for the synthesis of 2-formylbenzonitriles (2-cyano benzaldehydes) 4a–i

2-Formylbenzonitriles 4a–i were prepared according the procedure reported in literature, starting from 2-methyl benzonitriles, by hydrolysis of benzal bromides in water/dioxane system.¹⁴

Pathway A: procedure for the preparation of racemic phthalide from 2-carbomethoxybenzaldehyde 3

A solution of isoindolinone 1 (0.1 mmol), potassium carbonate (0.5 equiv.) and 2-carbomethoxybenzaldehyde 2 (1.1 equiv.) in CH₃CN (2 mL) was stirred at room temperature for 1 h. The mixture was evaporated under reduced pressure, giving a white solid which was purified by chromatography on silica gel (hexane/ethyl acetate 8/2). Yield: 88%.

Pathway B: general procedure for the preparation of racemic imidates rac-5a–i from 2-formylbenzonitriles and preparation of phthalides rac-3a–j by hydrolysis of imidates

A solution of isoindolinone 1 (0.1 mmol), potassium carbonate (0.5 equiv.) and 2-formylbenzonitriles 4a–i (1.1 equiv.) in CH₃CN (2 mL) was stirred at room temperature till starting material disappeared (1–2 h). The mixture was filtered, evaporated under reduced pressure, then suspended in THF (2 mL)/HCl 0.5 M (1 mL) and the reaction mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and extracted three times with dichloromethane affording a white solid which was purified by chromatography on silica gel (hexane/ethyl acetate 7/3). Yields for the obtained hybrids are in the range 75–93%.

General procedure for organocatalytic asymmetric synthesis of imidates 5a–j

A solution of isoindolinone 1 (0.058 mmol), Takemoto catalyst 8 (10% mol) and 2-formylbenzonitriles 4a–i (1.1 equiv.) in p-xylene (2.5 mL) were stirred at 20 °C till starting material disappeared. The mixture was directly purified by chromatography on silica gel (hexane/ethyl acetate 8/2 to ethyl acetate).

General procedure for the preparation of chiral phthalides 3a–i by hydrolysis of imidates 5a–i

Imidates 5a–i were suspended in THF (2 mL) and HCl 0.5 M (1 mL) was added and the reaction mixture was stirred at room temperature for 2 h. Solvent was removed under reduced pressure and extracted three times with dichloromethane affording a white solid which was purified by chromatography on silica gel (hexane/ethyl acetate 7/3).

Characterization of the imidate ethyl 1-(1,3-dihydro-1-iminoisobenzofuran-3-yl)-3-oxoisoindoline-1-carboxylate 5a

White solid. Yield: 90%. Mp: 198 °C decomp. (CHCl₃/hexane). [α]¹⁴_D: +220 (c 0.1, CHCl₃). ¹H-NMR (400 MHz, CDCl₃): 7.94 (d, 1H, J = 7.5 Hz), 7.83 (d, 1H, J = 7.5 Hz), 7.74 (t, 1H, J = 7.4 Hz), 7.67–7.64 (m, 2H), 7.19 (bt, 1H, J = 8.0 Hz), 7.06 (t, 1H, J = 7.5 Hz), 6.36 (s, 1H), 5.62 (d, 1H, J = 7.7 Hz), 4.41–4.31 (m, 2H), 1.36 (t, 3H, J = 7.1 Hz). ¹³C-NMR (75 MHz, CDCl₃): 169.6, 168.5, 166.8, 140.5, 140.1, 132.5, 132.4, 131.7, 130.4, 129.9, 129.8, 124.5, 124.3, 123.9, 121.1, 85.8, 69.9, 63.0, 14.0. HRMS (ESI) calcd for C₁₉H₁₆N₂O₄ + H⁺: 337.11828, found 337.11820. Enantiomeric excesses were determined after hydrolysis.

Characterization of the phthalides 3

Ethyl 1-(1,3-dihydro-1-oxoisobenzofuran-3-yl)-3-oxoisoindoline-1-carboxylate 3a. Yield after 2 steps: 86%. Mp: 217 °C (decomp.); [α]¹⁴_D: +121.9 (c 0.12, CHCl₃). ¹H-NMR (300 MHz, CDCl₃): 7.99 (d, 1H, J = 7.56 Hz), 7.88–7.68 (m, 4H), 7.45 (t, 1H, J = 7.81 Hz), 7.25 (t, 1H, J = 7.38 Hz), 6.46 (bs, 1H, NH), 6.37 (s, 1H), 5.79 (d, 1H, J = 7.62 Hz), 4.37–4.31 (m, 2H), 1.34 (t, 3H, J = 7.14 Hz). ¹³C-NMR (75 MHz, CDCl₃): 169.3, 169.0, 168.0, 143.2, 140.2, 133.8, 132.9, 131.8, 130.7, 130.2, 126.8, 126.0, 124.7, 123.3, 121.7, 83.2, 69.0, 63.4, 13.9. HRMS (ESI): m/z calcd for C₁₉H₁₅NO₅ + H⁺: 338.10231, found: 338.10240. Anal. calcd for C₁₉H₁₅NO₅: C 67.65, H 4.48, N 4.15. Found: C 67.41, H 4.32, N 4.11. Chiral HPLC: IA-3 column, hexane-iPrOH (70 : 3), flow: 0.6 mL min⁻¹, t: 24.9 min and 31.7 min.

Ethyl 1-(6-fluoro-1,3-dihydro-1-oxoisobenzofuran-3-yl)-3-oxoisoindoline-1-carboxylate 3b. Yield after 2 steps: 90%. Mp: 173 °C (decomp.); [α]²⁰_D: +149.1 (c 0.1, CHCl₃). ¹H-NMR (300 MHz, CDCl₃): 7.97 (d, 1H, J = 10.0 Hz), 7.80 (q, 2H, J = 7.5 Hz), 7.69 (t, 1H, J = 7.5 Hz), 7.51 (d, 1H, J = 6.9 Hz), 6.99–6.93 (m, 1H), 6.52 (bs, 1H, NH), 6.35 (s, 1H), 5.74 (dd, 1H, J = 3.0 Hz, 8.1 Hz), 4.38–4.33 (m, 2H), 1.35 (t, 3H, J = 7.2 Hz). ¹³C-NMR (75 MHz, CDCl₃): 169.5, 168.1, 168.0, 163.2 (J₁ C–F = 250 Hz), 140.3, 138.9, 133.3, 131.9, 131.2, 129.4 (J₃ C–F = 9 Hz), 125.1, 123.8 (J₃ C–F = 9 Hz), 123.5, 122.0 (J₂ C–F = 23 Hz), 112.8 (J₂ C–F = 23 Hz), 83.4, 69.1, 63.8, 14.2. HRMS (ESI): m/z calcd for C₁₉H₁₄FNO₅ + H⁺: 356.09288, found: 356.09281. Chiral HPLC: IA-3 column, hexane-iPrOH (70 : 30), flow: 0.6 mL min⁻¹, t: 30.1 min and 34.4 min. Anal. calcd for C₁₉H₁₄FNO₅: C 64.23, H 3.87, N 3.94. Found: C 64.31, H 3.62, N 3.71.

Ethyl 1-(6-chloro-1,3-dihydro-1-oxoisobenzofuran-3-yl)-3-oxoisoindoline-1-carboxylate 3c. Yield after 2 steps: 93%. 224 °C (decomp.); [α]²⁰_D: +128.3 (c 0.43, CHCl₃). ¹H-NMR (300 MHz, CDCl₃): 7.97 (d, 1H, J = 8.76 Hz), 7.85–7.83 (m, 3H), 7.77–7.72 (m, 1H), 7.19 (d, 1H, J = 8.76 Hz), 6.36 (bs, 1H, NH), 6.32 (s, 1H), 5.68 (d, 1H, J = 8.04 Hz), 4.38–4.33 (m, 2H), 1.35 (t, 3H, J = 7.17 Hz). ¹³C-NMR (60 MHz, CDCl₃): 169.6, 168.1, 167.8, 141.6, 140.3, 136.9, 134.5, 133.4, 131.9, 131.2, 129.0, 126.3, 125.2, 123.6, 123.2, 83.4, 69.1, 63.8, 14.3. HRMS (ESI): m/z calcd for C₁₉H₁₄ClNO₅ + H⁺: 372.06333, found: 372.06345. Chiral HPLC: AD column, hexane-iPrOH (8 : 2), flow: 0.6 mL min⁻¹, t: 38.7 min and 45.4 min. Anal. calcd for C₁₉H₁₄ClNO₅: C 61.38, H 3.80, N 3.77. Found: C 61.31, H 3.62, N 3.61.

Ethyl 1-(6-bromo-1,3-dihydo-1-oxoisobenzofuran-3-yl)-3-oxoisoindoline-1-carboxylate 3d. Yield after 2 steps: 86%. Mp: 193–194 °C; [α]¹⁴_D: +107.8 (c 0.5, CHCl₃). ¹H-NMR (300 MHz, CDCl₃): 7.97 (t, 1H, J = 7.65 Hz), 7.79–7.85 (m, 3H), 7.69–7.77 (m, 1H), 7.35 (dd, 1H, J = 1.74 Hz, 8.18 Hz), 6.43 (bs, 1H, NH), 6.33 (s, 1H), 5.63 (d, 1H, J = 8.19 Hz), 4.38–4.31 (m, 2H), 1.35 (t, 3H, J = 7.25 Hz). ¹³C-NMR (60 MHz, CDCl₃): 169.6, 168.1, 167.7, 142.1, 140.3, 137.2, 133.4, 131.9, 131.2, 129.3, 129.2, 125.2, 124.7, 123.6, 123.4, 83.5, 69.1, 63.8, 14.3. HRMS (ESI): m/z calcd for C₁₉H₁₄BrNO₅ + H⁺: 416.01281, found 416.01277. Anal. calcd for C₁₉H₁₄BrNO₅: C 54.83, H 3.39, N 3.37. Found: C 54.71, H 3.32, N 3.51. Chiral HPLC: IA-3 column, hexane-iPrOH (70 : 30), flow: 0.6 mL min⁻¹, t: 21.7 min and 24.7 min.

Ethyl 1-(6-iodo-1,3-dihydro-1-oxoisobenzofuran-3-yl)-3-oxoisoindoline-1-carboxylate 3e. Yield after 2 steps: 90%. Mp: 211–213 °C; [α]¹⁸_D: +81.4 (c 0.5, CHCl₃). ¹H-NMR (400 MHz, CDCl₃): 8.18 (s, 1H), 7.96 (d, 1H, J = 7.6 Hz), 7.84–7.76 (m, 2H), 7.70–7.68 (m, 1H), 7.53 (d, 1H, J = 8.1 Hz), 6.50 (bs, 1H, NH), 6.32 (s, 1H), 5.49 (d, 1H, J = 8.2 Hz), 4.39–4.30 (m, 2H), 1.34 (t, 3H, J = 7.1 Hz). ¹³C-NMR (75 MHz, CDCl₃): 169.3, 167.8, 167.3, 142.6, 142.5, 139.9, 135.0, 133.1, 131.7, 130.9, 128.9, 124.9, 123.3, 123.2, 95.6, 83.3, 68.7, 63.6, 13.9. HRMS (ESI): m/z calcd for C₁₉H₁₄INO₅ + H⁺: 463.99894, found: 463.99874. Chiral HPLC: IA-3 column, hexane-iPrOH (70 : 30), flow: 0.6 mL min⁻¹, t: 16.9 min and 20.0 min. Anal. calcd for C₁₉H₁₄INO₅: C 49.26, H 3.05, N 3.02. Found: C 49.41, H 3.22, N 3.35.

Ethyl 1-(6-methoxy-1,3-dihydro-1-oxoisobenzofuran-3-yl)-3-oxoisoindoline-1-carboxylate 3f. Yield after 2 steps: 93%. Mp: 131–133 °C; [α]²⁰_D: +77.2 (c 0.4, CHCl₃). ¹H-NMR (300 MHz, CDCl₃): 7.76 (d, 1H, J = 6.3 Hz), 7.65–7.70 (m, 2H), 7.68–7.65 (m, 1H), 7.28 (s, 1H), 6.78 (dd, 1H, J = 2.4 Hz, 8.4 Hz), 6.38 (bs, 1H, NH), 6.31 (s, 1H), 5.63 (d, 1H, J = 8.7 Hz), 4.40–4.29 (m, 2H), 3.78 (s, 3H), 1.35 (t, 3H, J = 6.9 Hz). ¹³C-NMR (60 MHz, CDCl₃): 169.3, 169.0, 168.0, 161.2, 140.2, 135.3, 132.8, 132.0, 131.8, 130.7, 128.5, 128.3, 124.7, 123.3, 107.9, 83.1, 68.9, 63.4, 55.6, 13.9. HRMS (ESI): m/z calcd C₂₀H₁₇NO₆ + H⁺: 368.11286, found: 368.11282. Anal. calcd for C₂₀H₁₇NO₆: C 65.39, H 4.66, N 3.81. Found: C 65.31, H 4.52, N 3.75. Chiral HPLC: IA-3 column, hexane-iPrOH (70 : 30), flow: 0.6 mL min⁻¹, t: 25.6 min and 31.2 min.

Ethyl 1-(6-nitro-1,3-dihydro-1-oxoisobenzofuran-3-yl)-3-oxoisoindoline-1-carboxylate 3g. Yield after 2 steps: 80%. Mp: 198 °C (decomp.); [α]²⁰_D: +64.4 (c 0.9, CHCl₃). ¹H-NMR (300 MHz, CDCl₃): 8.69 (s, 1H), 8.12 (dd, 1H, J = 1.8, 8.4 Hz), 8.01 (d, 1H, J = 7.6 Hz), 7.87–7.82 (m, 2H), 7.76–7.72 (m, 1H), 6.49 (s, 1H), 6.40 (bs, 1H, NH), 5.93 (d, 1H, J = 8.1 Hz), 4.43–4.33 (m, 2H), 1.37 (t, 3H, J = 7.1 Hz). ¹³C-NMR (60 MHz, CDCl₃): 169.4, 167.5, 166.5, 149.5, 148.5, 139.6, 133.3, 132.3, 131.7, 131.2, 129.2, 128.8, 125.1, 124.0, 123.6, 123.3, 123.1, 121.4, 83.4, 68.9, 63.8, 14.0. HRMS (ESI): m/z calcd for C₁₉H₁₄N₂O₇ + H⁺: 383.08738, found 383.08731. Chiral HPLC: AD column, hexane-iPrOH (70 : 30), flow: 0.8 mL min⁻¹, t: 25.9 min and 36.3 min. Anal. calcd for C₁₉H₁₄N₂O₇: C 59.69, H 3.69, N 7.33. Found: C 59.35, H 3.52, N 7.45.

Ethyl 1-(6-phenyl-1,3-dihydro-1-oxoisobenzofuran-3-yl)-3-oxoisoindoline-1-carboxylate 3h. Yield after 2 steps: 85%. Mp: 195–196 °C; [α]²⁰_D: +169.4 (c 0.43, CHCl₃). ¹H-NMR (400 MHz, CDCl₃): 8.04 (t, 2H, J = 9.0 Hz), 7.84 (q, 2H, J = 9.0 Hz), 7.73 (t, 1H, J = 6.0 Hz), 7.51–7.44 (m, 6H), 6.49 (s, 1H), 6.48 (s, 1H), 5.84 (d, 1H, J = 8.0 Hz), 4.43–4.33 (m, 2H), 1.38 (t, 3H, J = 7.5 Hz). ¹³C-NMR (75 MHz, CDCl₃): 169.6, 169.2, 168.3, 143.9, 142.1, 140.1, 138.9, 133.2, 132.0, 131.0, 129.2, 128.5, 127.8, 127.4, 125.1, 124.4, 123.7, 122.3, 83.5, 69.3, 63.7, 14.2. HRMS (ESI): m/z calcd for C₂₅H₁₉NO₅ + H⁺: 414.13367, found 414.13358. Anal. calcd for C₂₅H₁₉NO₅: C 72.63, H 4.63, N 3.39. Found: C 72.55, H 4.52, N 3.67. Chiral HPLC: IA-3 column, hexane-iPrOH (7 : 3), flow: 0.6 mL min⁻¹, t: 29.7 min and 49.6 min.

Ethyl 1-(6-(3,4 dimethoxy)phenyl-1,3-dihydro-1-oxoisobenzofuran-3-yl)-3-oxoisoindoline-1-carboxylate 3i. Yield after 2 steps: 80% as a waxy solid; [α]²⁰_D: +48.4 (c 057, CHCl₃). ¹H-NMR (400 MHz, CDCl₃): 7.89 (t, 2H, J = 8.0 Hz), 7.87–7.84 (m, 3H), 7.81 (t, 1H, J = 8.0 Hz), 7.72 (t, 1H, J = 8.0 Hz), 7.64 (d, 1H, J = 8.0 Hz), 7.52–7.48 (m, 2H), 7.44–7.40 (m, 2H), 7.33 (d, 1H, J = 8.0 Hz), 6.43 (s, 2H), 5.92 (d, 1H, J = 8.0 Hz), 4.44–4.34 (m, 2H), 1.38 (t, 3H, J = 8.0 Hz). ¹³C-NMR (100 MHz): 170.7, 170.2, 169.4, 144.5, 143.4, 141.6, 138.8, 137.2, 134.9, 134.3, 133.1, 132.2, 132.1, 131.3, 129.8, 129.7, 128.6, 128.5, 127.8, 127.3, 126.5, 126.3, 126.2, 124.7, 123.0, 84.6, 70.3, 64.8, 15.3. HRMS (ESI): m/z calcd for C₂₅H₂₁NO₅ + H⁺: 464.14925, found 464.14933. Anal. calcd for C₂₉H₂₁NO₅: C 75.15, H 4.57, N 3.02. Found: C 75.38, H 4.49, N 3.27. Chiral HPLC: IA-3 column, hexane-iPrOH (8 : 2), flow: 0.8 mL min⁻¹, t: 30.0 min and 33.7 min.

Ethyl 5-bromo-1-(1,3-dihydro-1-oxoisobenzofuran-3-yl)-3-oxoisoindoline-1-carboxylate 3j. Yield after 2 steps: 81%. Mp: 250 °C (dec.) [α]²⁰_D: +168.0 (c 0.25, CHCl₃). ¹H-NMR (300 MHz, CDCl₃): 7.91–7.86 (m, 4), 7.50 (t, 1H, J = 7.5 Hz), 7.36 (t, 1H, J = 6.0 Hz), 6.46 (bs, 1H, NH), 6.34 (s, 1H), 5.97 (d, 1H, J = 9.0 Hz), 4.44–4.28 (m, 2H), 1.36 (t, 3H, J = 7.5 Hz). ¹³C-NMR (75 MHz, CDCl₃): 169.1, 168.0, 167.8, 143.2, 139.1, 136.2, 134.3, 134.0, 130.6, 128.2, 127.0, 126.5, 125.4, 125.2, 121.9, 83.1, 69.2, 63.9, 14.2. HRMS (ESI): m/z calcd for C₁₉H₁₄BrNO₅ + H⁺: 416.01281, found 416.01287. Chiral HPLC: IA-3 column, hexane-iPrOH (7 : 3), flow: 0.6 mL min⁻¹, t: 28.5 min and 31.6 min. Anal. calcd for C₁₉H₁₄BrNO₅: C 54.83, H 3.39, N 3.37. Found: C 54.79, H 3.32, N 3.49.

Conclusions

In conclusion, suitable nucleophilic isoindolinones, activated in 3-position by an ester group, allow the access to new heterocyclic hybrids isoindolinone-imidates and isoindolinone-phthalides with contiguous tetra- and tri-substituted stereocenters via an asymmetric aldol initiated organocascade reaction with 2-cyano benzaldehydes. The best results were obtained in the presence of thiourea-1,2-diamine-cyclohexane derived organocatalyst, leading to the target compounds up to 97/3 er, dr > 20/1 and very good yields. In comparison, the use of chiral ammonium salt catalysis and of 2-formyl-methylbenzoate as electrophile was less promising, even though these alternative systems could not be excluded in future developments of this powerful synthetic strategy.

We are currently evaluating extensions of this methodology in the asymmetric synthesis of related compounds and biological investigations of the molecules herein reported are in course.

Acknowledgements

This research was funded by Region Campania under POR Campania FESR 2007–2013 – O.O. 2.1 (FarmaBioNet), by MIUR and University of Salerno. We also acknowledge Dr Patrizia Iannece for HR-MS analysis.

References

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra14041f

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