Mol Divers DOI 10.1007/s11030-013-9502-6

FULL-LENGTH PAPER

Combined electrochemical/chemical methods for the synthesis and the molecular diversifying of isoindolinone-based heterocyclic scaffolds Laura Palombi · Antonia Di Mola · Chiara Vignes · Antonio Massa

Received: 11 November 2013 / Accepted: 23 December 2013 © Springer Science+Business Media Dordrecht 2014

Abstract By means of C–H acids activation on Pt-cathode, an electrochemically initiated strategy aimed to developing a diversity-oriented synthesis based on the isoindolinone nucleus has been established. Conveniently, the achievement of a small library of new heterocycle-fused isoindolinone compounds with potential interest for drug design was carried out by using tandem reactions and one-pot sequential processes. Keywords Diversity-oriented synthesis · DOS Electrosynthesis · Isoindolinones · Hemiaminals · Imides · N -acyliminium · Electron-rich alkenes oxidation

Introduction As well documented by the recent literature in the field, a new way to effectively address drug discovery is currently based on the concept of diversity-oriented synthesis (DOS) [1– 4], an innovative philosophy conceived as the development of strategies/methodologies and technologies that enables a rapid increase in the structural complexity and molecular diversity, of pharmaceutically interesting heterocyclic scaffolds. Among biologically active heterocycles, isoindolinone derivatives constitute a large family of compounds occurring both in natural products and synthetic pharmaceutical Electronic supplementary material The online version of this article (doi:10.1007/s11030-013-9502-6) contains supplementary material, which is available to authorized users. L. Palombi (B) · A. Di Mola · C. Vignes · A. Massa Dipartimento di Chimica e Biologia, Università di Salerno, Via Giovanni Paolo II, 132-84084 Fisciano, SA, Italy e-mail: [email protected]

agents [5]. Due to their relevance in medicinal chemistry, considerable research efforts have been directed to the attainment of these interesting N -heterocyclic scaffolds and their related structures. Indeed, a large number of methods has been reported so far to reach this goal, either via multistep processes [6–9] or via cascade [10–13] and multicomponent reactions [14–16] on suitable substrates. We also recently reported short and efficient pathways to a 3-substituted isoindolinone nucleus by means of a cascade reaction between ocyanobenzaldehyde (o-CNC6 H4 CHO) and active methylene compounds [17,18]. As part of these studies, we demonstrated the effectiveness of a sequential one-pot conjugate addition to activated olefins providing highly functionalized isoindolinones and the direct, totally diastereoselective onepot access to tricyclic hemiaminal derivatives as a consequence of two-sequential tandem reactions (Scheme 1) [19]. In view of the presence of different structural features, reactive sites and stereogenic centers, compounds A–C can be perceived as versatile molecular platforms to enable a rapid access to a small library of multifunctional heterocyclic architectures with potential value for biological screening. We herein develop a divergent synthesis of isoindolinonic cores based on the molecular structures A–C as key components for branching networks of reactions.

Results and discussion Platform A: appendage diversity In a preliminary explorative effort, we were intrigued by the opportunity to introduce diverse chemical appendages on the isoindolinone skeleton A by means of the electrochemical activation of different nucleophiles, such as simple methyl ketones for which a base-catalyzed approach failed.

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Mol Divers O 1b

O

O

1c

1d

O O

O o-CNC6H4CHO

O

+

constant current electrolysis Pt-cathode, TEABF4

1e

NH

NH NH O 2e

O 3e

method A 2e (18% yield) 3e (22% yield; 2.5:1:1 d.r.) method B 2e (5% yield) 3e (36% yield; 2.5:1:1 d.r.)

Scheme 3 Electrochemical activation of acetophenone, double aldol and cascade reaction with o-CNC6 H4 CHO. For details regards Method A (solvent-free) and B see “Experimental” section

Scheme 1 Isoindolinones construction via cascade reaction of methylene active compounds and o-CNC6 H4 CHO

Scheme 2 Electrochemical activation of acetone and cascade reaction with o-CNC6 H4 CHO

The effectiveness of the electrochemical route was checked using acetone (1a) both as a reference compound and solvent, using standard electrochemical conditions previously tuned for methylene active compounds XCH2 Y (Scheme 1) [20,21]. As reported in Scheme 2, the isoindolinone derivative 2a was directly obtained with a 57 % isolated yield, by effecting a constant current electrolysis of 1a (0.05 electrons/molecule) in the cathodic compartment of a divided cell, using 1a both as solvent and reagent. Since the synthetic target 2a has been achieved in reasonable yield in a single step avoiding the use of bases or additional solvent and exploiting an efficient tandem process, this reaction can be certainly regarded as quite convenient both in terms of atom-economy and green chemistry and prompted us to test the reactivity of other methyl ketones under the same electrochemical conditions. Rather surprisingly, whereas compounds 1b–d were found completely unreactive, an unusual process of double aldol [22] and related cascade reactions leading to the bis-isoindolinone derivative 3e was observed for acetophenone 1e (Scheme 3). Although of limited value from a preparative point of view, this electrosynthetic method represents a unique single step approach to such a kind of derivatives, allowing an easy assembling of advanced heterocyclic architectures from readily available starting materials.

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Another synthetically interesting goal has been achieved by us through the electroactivation of the isocyanoacetate 4. As reported in Scheme 4, the electrolysis of 4 under classical electrochemical conditions led to the attainment of 5 as a mixture of diastereoisomers (d.r. evaluated by 1 H-NMR analysis) with an overall isolated yield of 43 %. This approach would pave the way towards a new class of chiral isoindolinone containing α-aminoacids. To further implement the molecular complexity of these compounds, according to the principles of DOS, we finally checked for an additional electro-activation of the molecular platform A under the same electrochemical conditions leading to their electrosynthesis (i.e., galvanostatic reduction on Pt-cathode in CH3 CN/TEABF4 system), to enable possible derivatizations with alkylating agents [23]. Based on our previous studies [24–26], both N–H and C–H acid activation should be expected using stoichiometric amount of current, enabling the potential access to several classes of compounds. As reported in Scheme 5, submitting the electroactivated isoindolinone A (X = CO2 Me) to the reaction with the representative reagent allyl bromide 6a, the most abundant C-alkylated product 7a could be isolated in 33 % yield. Indeed, this low-yielding result could be ascribed to a poor regioselective alkylation process, as the 1 H-NMR analysis of the crude reaction mixture showed the formation of both C-alkylated, N-alkylated, and dialkylated products against an incomplete conversion of the starting material A. Similarly, despite the presence of two bulky t-butyl groups on the 1,3-dicarbonyl moiety, a mixture of C-alkylated and Nalkylated products, along with unreacted starting material, was obtained by adding allyl bromide 6a to the electrolyzed solution of the isoindolinone A (X = COt2 Bu) (Scheme 5). On the other hand, the use of alkyl halides 6b–d suggests that the steric hindrance on the alkylating agent could be also an important factor in determining the preferential site for the alkylation of isoindolinones of type A since the N-alkylated

Mol Divers Scheme 4 Electrochemicallypromoted reaction between isocyanoacetate 4 and o-CNC6 H4 CHO

Scheme 5 Electrochemical activation of isoindolinone adducts A and alkylation with allyl bromide

products 8b–d are always isolated as the major regioisomers (Table 1). Although obtained with a modest selectivity, the isolated yields of these valuable N-alkylated products should still be regarded acceptable from a preparative point of view, given the ready availability of these compounds through a sequential process with outstanding features of step- and atomeconomy offered by the electrochemical technology.

Platforms B, C- skeletal, appendage, and stereochemical diversities Since the formation of N-alkylated products after the electroreduction of isoindolinone A suggested the possibility of other chemical transformations involving the electrogenerated amidic nitrogen anion, we focused efforts in trying an intramolecular cyclization of the isoindolinonic structures B, to get valuable tricyclic imides having a bridge nitrogen atom (Scheme 6). However, while testing various electrochemical and reaction conditions, only a 31 % yield in imide product 9a has been obtained because of a thermodynamic equilibrium threshold, rapidly reached after a ≈50 % of starting material conversion.

Noteworthy, neither the use of larger amounts of current quantity (up to 1 electron/molecule) or longer microwave irradiation times (as well as the use of conventional heating) allowed to shift the equilibrium of the reaction towards the formation of the expected product, while TLC and NMR analysis suggested a substantial decomposition of the reaction mixtures. Pleasantly, the goal of achieving the synthesis of tricyclic imides 9, was quickly and conveniently reached by pyridinium dichromate (PDC) oxidation [27] of the easily available molecular platforms C. As shown in Scheme 7, this synthetic route does not need the isolation or purification of the intermediate C, but only the sequential addition of reagents combining pot, atom, and step economies in a very efficient, high-yielding process. On the other hand, the presence of the hemiaminal functionality on the molecular platform C suggests a wide range of other synthetic applications and derivatizations. Consequently, in subsequent studies we decided to explore the potential of the hemiaminal group to design other interesting elaborations of this important class of tricyclic compounds. In particular, taking advantage of the N -acyl-iminium chemistry [28,29], we investigated first the reactivity of this electrophilic functionality towards a π -nucleophyle such as allyltrimethylsilane under Lewis acidic conditions [30,31]. As shown in Scheme 8, the BF3 -induced allylation of the molecular platform C satisfactorily afforded tricyclic amide 10 in good yield as a single diastereoisomer, thus proving the powerful stereocontrol of this C-nucleophilic addition. Noteworthy, the relative stereochemistry (R ∗ , R ∗ ) to the chiral centers, established by 1 H-NMR, is in agreement with previous literature reports on 2-oxaindolizidines [32]. Exploiting further the N -acyl-iminium chemistry, we successfully accomplished highly diastereoselective α-amido substitutions with oxygen containing nucleophilic com-

Table 1 N-alkylation of isoindolinone adduct A (X = COt2 Bu) with alkyl bromide 6b–d Entry

6

Product 8

React. time (h)

Yield (%)a

Conversion A (%)b

1

R = Benzyl (6b)

8b

2

40

74

2

R = β-Methyl allyl (6c)

8c

2

45

72

3

R = Geranyl (6d)

8d

3

54

77

a b

The yields refer to isolated products Conversion has been calculated on the basis of the starting material recovered after column

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Mol Divers Scheme 6 Electrochemically/microwaveinduced cyclization via intramolecular transamidation of Michael adducts B

Scheme 7 One-pot access to tricyclic imides via sequential electrochemically induced synthesis of tricyclic hemiaminals and PDC oxidation

pounds 11a–c, thereby widening the molecular diversification of the molecular platform C by simply changing the reaction partners. As reported in Table 2, under acidic conditions for 10-camphorsulfonic acid (CSA), new hydroperoxyand peroxy-hemiaminals 12 have been achieved in very satisfactory yields and complete diasastereoselectivity, in almost all the cases. On the other hand, during these experiments substrate C also revealed a tendency to undergo dehydration reac-

Scheme 8 BF3 -OEt2 -induced allylation of molecular platform C

Table 2 CSA-induced α-amido substitutions with peroxides 11

Entry

C

1

X = CO2 Me

2 3 4 5

X = COt2 Bu X = CO2 Me X = CO2 Me X = CO2 Me

11

12 Yieldb

12 d.r.c >98:2

R=H

85 %

11aa

12a

R=H

80 %

11aa

12a

R = t Bu

88 %

11b

12b

R = C6 H5 C(CH3 )2

78 %

11b

12c

R = m-Cl-C6 H4 CO



>98:2 >98:2 >98:2 –

11c a

In this case the adduct urea–H2 O2 (UHP) has been used as nucleophile The yields refer to isolated product c The 1 H- and 13 C-NMR indicate the presence of only one diastereoisomer, the relative stereochemistry (R ∗ , R ∗ ) to the chiral centers has been assigned by analysis of the coupling constants for the H-atom on Cα (The values of J for products 12 fall in the range of 2–2.8 Hz, strongly suggesting that this hydrogen atom is located in equatorial position (see “Experimental” section) b

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Mol Divers Scheme 9 One-pot access to tricyclic enamides D

Scheme 11 Electrochemically induced methanolysis of 13a

Scheme 10 Regio- and stereoselective access to triclyclic monoprotected cis-diol 13a

Fig. 1 Stereochemical relationship between the substituents at the chiral centers deduced by the measurements of the coupling constants

tion, yielding the derivative D that incorporates the enamidic group, useful for further molecular processing. Conveniently, enamides D could be obtained in high yields by means of the expedient one-pot procedure reported in Scheme 9. In view of the easy access to the compound D, we were intrigued by the chance of a double functionalization of the six-membered heterocyclic ring. In particular, given the synthetic relevance of epoxy derivatives and diols, we decided to test the reactivity of the enamide D versus MCPBA, a classical epoxidizing reagent for electron-rich double bonds [33]. As reported in Scheme 10, in a preliminary experiment performed with MCPBA in CH2 Cl2 , enamide D provided the mono-protected cis-diol 13a as the exclusive reaction product. This product could be explained with the reaction pathway described below, which shows the regio- and stereoselective attack of the 3-Cl-benzoate anion to the N -acyliminium intermediate. Nicely, an electrochemically induced methanolysis allowed alcohol deprotection and the formation of the respective cis-diol 14 in quantitative yield (Scheme 11). Interestingly, the 1 H-NMR analysis of 14 demonstrated a cis stereochemical relationship of the two substituents and the axial position for the one at the Cα (Fig. 1), so that the relative configuration could be assigned as (R ∗ , R ∗ , R ∗ ).

Scheme 12 MCPBA oxidation of D in the presence of K2 CO3

In order to avoid an epoxide ring opening, the MCPBA oxidation was performed in presence of bases such as NaHCO3 or Na2 CO3 [34]. However, while varying conditions and experimental parameters, the formation of the expected epoxide was not observed. Rather, the presence of Na2 CO3 , caused a Cα–O · · · Cβ–O- benzoyl shift and, as a consequence, the attainment of the corresponding regioisomer 13b (Scheme 12). The possibility to alternatively get both the regioisomers 13a and 13b by simply varying the reaction conditions could be advantageously exploited for the selective Cα or Cβ oxi-

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Mol Divers Scheme 13 Regioselective MCPBA and PDC oxidations of D

dation with PDC, allowing a further molecular diversifying of these interesting tricyclic structures (Scheme 13). Notewhorthy, the use of epoxiding agents as t-butyl hydroperoxide and cumyl hydroperoxide in combining with acidic catalysts such as CSA or p-TsOH, led to the corresponding peroxides 12 as exclusive products due to a typical double-bond addition pathway.

using an electrospray spectrometer, waters 4 micro quadrupole. Elemental analyses were performed with FLASHEA 1112 series-Thermo Scientific for CHNS-O apparatus. The substrates A, B, and C were synthesized according to previous report and gave spectral and analytical data as reported [19]. 3-(2-Oxopropyl)isoindolin-1-one (1a)

Conclusions In conclusion, focusing on the isoindolinonic nucleus, a collection of novel heterocyclic products that contains a diverse range of molecular shapes, appendages and stereoselectively generated chiral centers has been conveniently achieved by combining the electrochemical strategy and traditional chemical methods in sequential one-pot processes. The convenient exploiting of N -acyliminium chemistry, allowed to highlight an unexpected reactivity of MCPBA on the molecular platform C, and a new class of cis-diols containing the isoindolinone nucleus has been easily achieved.

Experimental section General informations Constant current electrolyses were performed using using an Amel Model 552 potentiostat. The experiments were carried out in an hand-made U-divided glass cell as described elsewhere [21]. Platinum spirals (apparent area: ≈1 cm2 ) were used as anode and cathode. In all the experiments the anolyte was constituted by a solution of TEABF4 0.1 M in CH3 CN. All the reactions were monitored by thin layer chromatography (TLC) using Merck Silica Gel 60 F254 plates and were visualized by fluorescence quenching at 254 nm. Column chromatographic purification of products was carried out using silica gel 60 (70–230 mesh, Merck) using a mixture of CHCl3 : AcEt as eluents. The NMR spectra were recorded on Bruker spectrometers (400, 300, 250 MHz, 1 H; 100, 75, 62,5 MHz 13 C). Spectra were referenced to residual CHCl3 (7.26 ppm, 1H; 77.00 ppm, 13 C) or CD3 CN (1.94 ppm, 1 H; 118.0 and 1.4 ppm, 13 C) when indicated. Coupling constants J are reported in Hz. Mass spectral analyses were carried out

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A solution of o-CNC6 H4 CHO (0.091 mmol, 12 mg) and TEABF4 (0.05 mmol) in acetone (2a) (0.25 mL) was electrolyzed at the cathode compartment of a divided cell under galvanostatic conditions (spiral Pt-anode and -cathode, 1 cm2 ; I = 10 mA; Q = 0.05 electrons/molecule of o-CNC6 H4 CHO). At the end of the electrolysis, the reaction was prolonged at r.t. under magnetic stirring until TLC disappearance of o-CNC6 H4 CHO. The mixture was then concentrated in vacuum and purified by flash chromatography. 1a (10 mg) was obtained as a white solid (spectral and analytical data match with those reported in the literature) [35]. 3-(2-Oxo-2-phenylethyl)isoindolin-1-one (1e) and 3,3 -(2-oxo-2-phenylethane-1,1-diyl)bis(isoindolin-1-one) (3e) Method A A solution of o-CNC6 H4 CHO (65 mg, 0.49 mmol) and TEABF4 (10 mg, 0.05 mmol) in acetophenone (2e) (154 mg, 0.15 mL, 1.28 mmol) was electrolyzed at the cathode compartment of a divided cell under galvanostatic conditions (spiral Pt-anode and cathode, 1 cm2 ; I = 10 mA; Q = 0.1 electrons/molecule of o-CNC6 H4 CHO). At the end of the electrolysis, the reaction was prolonged at r.t. under magnetic stirring for 2 h. The mixture was then concentrated in vacuum and purified by flash chromatography. 1e (22 mg, 18 % yield): pale-yellow solid, MS (ESI) m/z: 274 (M+Na+ ). 1 H-NMR : δ 3.10 (1H, dd, J1 = 10.1; J2 = 18.2), 3.73 (1H, dd, J1 = 3.3; J2 = 18.2), 5.15 (1H, dd J1 = 10.1; J2 = 3.3), 6.79 (1H, s), 7.46–7.97 (9H, m). 13 C-NMR: 197.9, 169.9, 146.5, 136.0, 133.9 (2C), 131.9 (2C), 128.8, 128.5 (2C), 128.1, 124.2, 122.3, 52.4, 44.0. Anal. Calcd. for C16 H13 NO2 : C, 76.48; H, 5.21; N, 5.57; O, 12.73. Found: C, 76.53; H, 5.19; N, 5.54. 3e (21 mg, 22 % yield) white solid, MS (ESI) m/z: 382. 1 H-NMR (diagnostic signals for the major diastereoisomer): 7.82–7.10

Mol Divers

(13H, m), 5.26–5.25 (1H, ad), 4.67–4.66 (1H, bs), 4.80 (1H, bs). 13 C-NMR (mixture of 3 diastereoisomers): 200.3, 199.6, 199.6, 171.2 (2C), 170.7, 170.4, 170.3 (2C), 145.3–122.5 (54C), 62.7 (2C), 62.4, 56.7, 55.6, 54.4, 53.5, 53.4, 52.7. Anal. Calcd. for C24 H18 N2 O3 : C, 75.38; H, 4.74; N, 7.33; O, 12.55. Found: C, 75.42; H, 4.71; N, 7.30. Method B A solution of o-CNC6 H4 CHO (65 mg, 0.49 mmol), acetophenone (2e) (72 mg, 0.07 mL, 0.6 mmol), and TEABF4 (11 mg, 0.05 mmol) in CH3 CN (0.07 mL) was electrolyzed at the cathode compartment of a divided cell under galvanostatic conditions (Pt-anode and -cathode; I = 10 mA; Q = 0.05 electrons/molecule of o-CNC6 H4 CHO). At the end of the electrolysis, the reaction was prolonged at r.t. under magnetic stirring for 2 h. The mixture was then concentrated in vacuum and purified by flash chromatography. 1e (6 mg, 5 % yield).3e (34 mg, 36 % yield). Methyl-2-isocyano-2-(3-oxoisoindolin-1-yl)acetate (5) A solution of o-CNC6 H4 CHO (12 mg, 0.092 mmol), 4 (10 mg, 0.1 mmol), and TEABF4 (11 mg, 0.05 mmol) in CH3 CN (0.15 mL) was electrolyzed at the cathode compartment of a divided cell under galvanostatic conditions (Pt-anode and -cathode; I = 10 mA; Q = 0.1 electrons/molecule of o-CNC6 H4 CHO). At the end of the electrolysis, the mixture was concentrated in vacuum and purified by flash chromatography. 5 (9 mg, 43 % yield, mixture of diastereoisomers), orange solid, MS (ESI) m/z: 231.07 (M+1). 1 H-NMR (diagnostic signals for the major diastereoisomer): 7.92–7.46 (4H, m), 7.05 (1H, s), 5.08 (1H, d, J = 6.7), 4.43 (1H, d, J = 6.7) 3.93 (3H, s). 13 C-NMR (mixture of diastereoisomers): 170.4, 169.8, 165.2, 164.9, 161.3, 161.1, 142.7, 141.4, 132.8, 132.5, 132.4, 132.3, 129.6, 129.4, 123.4, 123.3, 123.2, 123.2, 78.1 (2C), 59.3, 56.6, 53.7, 53.5. Anal. Calcd. for C12 H10 N2 O3 : C, 62.61; H, 4.38; N, 12.17; O, 20.85. Found: C, 62.63; H, 4.40; N, 12.16.

Dimethyl-2-allyl-2-(3-oxoisoindolin-1-yl)malonate (7a) (5 mg, 33 % yield): white solid, MS (ESI) m/z: 304.11 (M+1) 1 H-NMR: 7.85 (1H, d, J = 6.8), 7.54-7.50 (2H, m), 7.21 (1H, d, J = 6.8), 6.94 (1H, s), 5.73–5.63 (1H, m), 5.29 (1H, s), 5.02–4.94 (2H, m), 3.86 (3H, s), 3.68 (3H, s), 2.60 (1H, dd, J1 = 14.8, J2 = 6.8), 2.34 (1H, dd, J1 = 14.8, J2 = 8.0). 13 C-NMR: 170.0, 169.7, 169.6, 142.2, 132.9, 132.1, 131.9, 129.1, 124.0, 123.2, 118.9, 61.2, 58.3, 52.9, 52.9, 34.2. Anal. Calcd. for C16 H17 NO5 : C, 63.36; H, 5.65; N, 4.62; O, 26.37. Found: C, 63.40; H, 5.64; N, 4.63. Di-tert-butyl-2-(2-allyl-3-oxoisoindolin-1-yl)malonate (8a) (5 mg, 27 % yield): white solid, MS (ESI) m/z: 388.21 (M+1). 1 H-NMR: 7.83 (1H, d, J = 7.2), 7.66 (1H, d, J = 7.2), 7.52–7.48 (2H, m), 5.91–5.78 (1H, m), 5.30– 5.23 (2H, m), 5.16 (1H, d, J = 3.2), 4.76 (1H, dd, J1 = 16.0, J2 = 4.4), 3.93 (1H, d, J = 3.2), 3.76 (1H, dd, J1 = 16.0, J2 = 7.6), 1.47 (9H, s), 1.11 (9H, s). 13 C-NMR: 168.1, 166.4, 165.2, 142.8, 132.8, 131.4, 128.4, 124.2, 123.3, 118.0, 82.9, 82.2, 57.6, 54.3, 42.6, 27.8 (3C), 27.2 (3C). Anal. Calcd. for C22 H29 NO5 : C, 68.20; H, 7.54; N, 3.61; O, 20.65. Found: C, 68.23; H, 7.59; N, 3.57. Di-tert-butyl-2-(2-benzyl-3-oxoisoindolin-1-yl)malonate (8b) (9 mg, 40 % yield): pale-yellow solid, MS (ESI) m/z: 388.21 (M+1). 1 H-NMR: 7.88–7.86 (1H, m), 7.64–7.49 (3H, m), 7.40–7.29 (5H, m), 5.50 (1H, d, J = 15.6), 4.96 (1H, d, J = 3.0), 4.17 (1H, d, J = 15.6), 3.96 (1H, d, J = 3.0), 1.45 (9H, s), 1.11 (9H, s). 13 C-NMR: 168.4, 166.4, 165.1, 143.0, 136.6, 132.5, 131.5, 128.8, 128.5, 128.0, 127.7, 124.4, 123.5, 82.8, 82.2, 57.3, 54.2, 43.7, 27.9 (3C), 27.4(3C). Anal. Calcd. for C22 H29 NO5 : C, 68.20; H, 7.54; N, 3.61; O, 20.65. Found: C, 68.24; H, 7.55; N, 3.59.

Typical experimental procedure for electro-induced alkylation of isoindolinones

Di-tert-butyl-2-(2-(β-methyl)-allyl-3-oxoisoindolin-1-yl)malonate (8c)

A solution of isoindolinone (A) (0.05 mmol) and TEABF4 (15 mg, 0.07 mmol) in CH3 CN (0.5 mL) was electrolyzed at the cathode compartment of a divided cell under galvanostatic conditions (Pt- anode and -cathode; I = 10 mA; Q = 1 electrons/molecule of A). At the end of the electrolysis, the alkylating agent (6a–d) (1.2 eq.) was added to the cathode compartment and the reaction was prolonged at r.t. under magnetic stirring for the time reported in Table 1. The mixture was then concentrated in vacuum and purified by flash chromatography.

(9 mg, 45 % yield): white solid, MS (ESI) m/z: 402.22 (M+1) 1 H-NMR: 7.85 (1H, d, J = 6.0), 7.67 (1H, d, J = 6.0) 7.55– 7.44 (2H, m), 5.06 (1H, d, J = 3.3), 4.94 (1H, bs) 4.87 (1H, bs), 4.75 (1H, d, J = 15.6), 3.95 (1H, d, J = 3.3) 3.66 (1H, d, J = 15.6), 1.69 (3H, s), 1.48 (9H, s), 1.08 (9H, s). 13 C-NMR (400 MHz, CDCl ): 168.3, 166.6, 142.9, 140.7, 3 132.5, 131.4, 128.5, 124.5, 123.4, 113.3, 82.8, 82.1, 57.6, 54.1, 45.9, 27.9, 27.3, 19.9. Anal. Calcd. for C23 H31 NO5 : C, 68.80; H, 7.78; N, 3.49; O, 19.92. Found: : C, 68.83; H, 7.80; N, 3.50.

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Mol Divers

Di-tert-butyl-2-(2-geranyl-3-oxoisoindolin-1-yl)malonate (8d) (13 mg, 54 % yield): pale-yellow solid, MS (ESI) m/z: 484.30. 1 H-NMR: 7.81 (1H, d, J = 7.5), 7.68 (1H, d, J = 7.5), 7.49–7.44 (2H, m), 5.25–5.21 (1H, m), 5.09 (1H, d, J = 2.7), 5.07–5.04 (1H, m), 4.71 (1H, dd, J1 = 15.5, J2 = 5.7), 3.92 (1H, d, J = 2.7), 3.80 (1H, dd, J1 = 15.5, J2 = 8.1), 2.08–1.98 (6H, m), 1.77 (3H, s), 1.65 (3H, s), 1.57 (3H, s), 1.50 (9H, s), 1.06 (9H, s). 13 C-NMR (300 MHz, CDCl3 ): 167.9, 166.7, 165.0, 142.8, 140.6, 132.9, 131.8, 131.1, 128.4, 124.4, 123.6, 123.1, 118.8, 82.7, 81.9, 57.6, 54.0, 39.5, 37.7, 27.9 (3C), 27.3 (3C), 26.3, 25.6, 17.6, 16.4. Anal. Calcd. for C29 H41 NO5 : C, 72.02; H, 8.55; N, 2.90; O, 16.54. Found: C, 72.06; H, 8.57; N, 2.85. Experimental procedure for electrochemically induced synthesis of tricyclic hemiaminals C and PDC oxidation A solution of 1 (0.1 mmol) and o-CNC6 H4 CHO (0.1 mmol) in CH3 CN/TEABF4 (0.15 mL/0.01 mmol) was electrolyzed at the cathode compartment of a divided cell under galvanostatic conditions (Pt-anode and -cathode; I = 10 mA; Q = 0.01 electrons/molecule of o-o-CNC6 H4 CHO). At the end of the electrolysis, the reaction was prolonged at r.t. under magnetic stirring until TLC disappearance of o-CNC6 H4 CHO; acrolein (0.12 mmol) was subsequently added. The mixture was kept under stirring up to complete the reaction (TLC disappearance of isoindolinone intermediate A) and concentrated in vacuum. The crude mixture was then dissolved in CH2 Cl2 (4 mL), molecular sieves and PDC (45 mg, 0.12 mmol) were added. After TLC disappearance of the intermediate C, MeOH (2 mL) was added, the mixture was filtered, concentrated in vacuum and purified by flash chromatography. Dimethyl-4,6-dioxo-3,4,6,10b-tetrahydropyrido[2,1a]isoindole-1,1(2H)-dicarboxylate (9a) (30 mg, 95 % yield): white solid, MS (ESI) m/z: 318 (M+1). 1 H-NMR: 7.94 (1H, d, J = 7.5), 7.65–7.53 (3H, m), 5.54 (1H, s), 3.94 (3H, s), 3.27 (3H, s), 2.85–2.50 (4H, m). 13 C-NMR: 170.7, 168.5, 168.4, 167.7, 141.2, 133.9, 130.4,129.4, 125.2, 124.5, 60.9, 57.7, 52.7, 53.5, 31.7, 29.0. Anal. Calcd. for C16 H15 NO6 : C, 60.57; H, 4.77; N, 4.41; O, 30.25. Found: C, 60.60; H, 4.80; N, 4.37. Di-tert-butyl-4,6-dioxo-3,4,6,10b-tetrahydrotetrahydropyrido [2,1-a]isoindole-1,1(2H)-dicarboxylate (9b)

(1H, m), 2.78–2.67 (2H, m), 2.37–2.32 (1H, m), 1.56 (9H, s), 0.96 (9H, s). 13 C-NMR: 171.1, 170.2, 167.6, 167.4, 143.8, 135.2, 132.0, 130.6, 126.9, 126.4, 85.1, 84.2, 62.7, 59.9, 32.9, 30.6, 29.4 (3C), 28.4 (3C). Anal. Calcd. for C22 H27 NO6 : C, 65.82; H, 6.78; N, 3.49; O, 23.91. Found: C, 65.80; H, 6.79; N, 3.51. Typical experimental procedure for the synthesis of allylated derivatives 10 In a flame-dried 2-necked round-bottomed flask, hemiaminal C (0.13 mmol) was added to activated molecular sieves in anhydrous CH2 Cl2 (3 mL). The mixture was kept under stirring in an atm. of N2 , at −40 ◦ C for 5 min and allyltrimethylsilane (0.39 mmol) and BF3 -OEt2 were successively added. After about 30 min, the reaction was quenched with aq. sat. NaHCO3 (6 mL), extracted twice with CH2 Cl2 (12 mL) and the combined organic extracts were dried (Na2 SO4 ). After the removal of the solvent under reduced pressure, the crude was purified by flash chromatography. Dimethyl-4-allyl-6-oxo-3,4,6,10b-tetrahydropyrido[2,1-a] isoindole-1,1(2H)-dicarboxylate (10a) (29 mg, 65 % yield): white solid, MS (ESI) m/z: 344 (M+1). 7.81 (1H, d, J = 6.6), 7.55–7.45 (3H, m), 5.85– 5.71 (1H, m), 5.07–5.00 (3H, m), 4.68–4.61 (1H, m), 3.89 (3H, s), 3.22 (3H, s), 2.54–2.34 (4H, m), 2.21–2.14 (2H, m). 13 C-NMR: 171.3, 167.7, 167.0, 143.0, 134.3, 132.4, 130.9, 128.3, 123.9, 123.3, 117.8, 57.8, 57.3, 53.1, 52.0, 46.0, 36.4, 27.6, 23.5. Anal. Calcd. for C19 H21 NO5 : C, 66.46; H, 6.16; N, 4.08; O, 23.30. Found: C, 66.50; H, 6.15; N, 4.10. 1 H-NMR:

Di-tert-butyl-4-allyl-6-oxo-3,4,6,10b-tetrahydropyrido[2,1a] isoindole-1,1(2H)-dicarboxylate (10b) (39 mg, 71 % yield): white solid, MS (ESI) m/z: 428 (M+1). 7.82–7.79 (1H, m), 7.64 (1H, d, J = 6.7), 7.54– 7.43 (2H, m),), 5.85–5.69 (1H, m), 5.05–4.97 (3H, m), 4.69– 4.60 (1H, m), 2.49–2.30 (4H, m), 2.02–2.00 (2H, m), 1.54 (9H, s), 0.91 (9H, s). 13 C-NMR: 170.4, 166.8, 166.4, 143.8, 134.5, 132.4, 130.7, 128.0, 125.4, 123.2, 117.6, 82.6, 81.6, 58.3, 57.3, 46.0, 36.4, 28.0, 27.9, 27.1, 23.3. Anal. Calcd. for C25 H33 NO5 : C, 70.23; H, 7.78; N, 3.28; O, 18.71. Found: C, 70.26; H, 7.80; N, 3.25.

1 H-NMR:

1,1 -(4-Allyl-6-oxo-1,2,3,4,6,10b-hexahydropyrido[2,1a]isoindole -1,1-diyl)bis(ethan-1-one) (10c) (28 mg, 70 % yield): white solid, MS (ESI) m/z: 312 (M+1).

(36 mg, 90 % yield): white solid, MS (ESI) m/z: 402 (M+1). 1 H-NMR: 7.95 (1H, d, J = 5.0), 7.74 (1H, J = 2.5), 7.66– 7.62 (1H, m), 7.55–7.51 (1H, m), 5.48 (1H, s), 2.93–2.88

123

1 H-NMR: 7.85–7.82 (1H, m), 7.53–7.43 (3H, m), 5.82–5.68

(1H, m), 5.22 (1H, s), 5.06–4.99 (2H, m), 4.63–4.55 (1H, m), 2.49–2.36 (2H, m), 2.24 (3H, s), 2.13–1.71 (4H, m), 1.44

Mol Divers

(3H, s). 13 C-NMR: 205.9, 204.6, 167.0, 142.9, 133.9, 132.7 131.5, 125.2, 123.9, 118.1, 69.9, 56.1, 46.7, 36.7, 30.7, 27.3, 27.1, 23.6. Anal. Calcd. for C19 H21 NO3 : C, 73.29; H, 6.80; N, 4.50; O, 15.41. Found: C, 73.31; H, 6.81; N, 4.47. Typical experimental procedure for CSA-inducedα-amido substitutions with peroxides A solution containing C (0.097 mmol), 11 (2 eq.), and (1R)(–)-10-camphorsulfonic acid (0.01 mmol) in CH2 Cl2 (1 mL) was kept under stirring at r.t. until TLC disappearance of the starting material. At the end of the reaction, aq. sat. NaHCO3 (2 mL) was added and the mixture extracted twice with CH2 Cl2 (6 mL). The combined organic extracts were dried over Na2 SO4 , concentrated in vacuum and purified by flash chromatography. Dimethyl-4-hydroperoxy-6-oxo-3,4,6,10b-tetrahydropyrido[2,1-a]isoindole-1,1(2H)-dicarboxylate (12a) (28 mg, 85 % yield): white solid, MS (ESI) m/z: 336 (M+1). 7.83 (1H, d, J = 7.5), 7.55–7.45 (3H, m), 6.04 (1H, d, J = 2.7), 5.35 (1H, s), 3.89 (3H, s), 3.25 (3H, s), 2.49–2.02 (4H, m). 13 C-NMR: 170.8, 168.3, 167.6, 143.4, 131.8, 131.3, 128.4, 124.3, 123.8, 80.6, 57.2, 57.0, 53.2, 52.1, 27.2, 23.6. Anal. Calcd. for C16 H17 NO7 : C, 57.31; H, 5.11; N, 4.18; O, 33.40. Found: C, 57.34; H, 5.10; N, 4.17.

1 H-NMR:

Di-tert-butyl- 4-hydroperoxy-6-oxo-3,4,6,10b-tetrahydropyrido [2,1-a]isoindole-1,1(2H)-dicarboxylate (12a ) (33 mg, 80 % yield): white solid, MS (ESI) m/z: 420 (M+1). 7.79 (1H, d, J = 7.6), 7.68 (1H, d, J = 7.6), 7.47–7.40 (2H, m), 6.04 (1H, d, J = 4.0), 5.33 (1H, s), 2.45–2.40 (2H, m), 2.09–1.99 (2H, m), 1.53 (9H, s), 0.89 (9H, s). 13 C-NMR: 169.8, 168.2, 166.3, 144.1, 131.6, 131.5, 128.2, 125.8, 123.7, 82.8, 81.8, 80.8, 57.8, 57.0, 27.8 (3C), 27.5, 27.2 (3C), 23.4. Anal. Calcd. for C22 H29 NO7 : C, 62.99; H, 6.97; N, 3.34; O, 26.70. Found: C, 63.02; H, 6.99; N, 3.32. 1 H-NMR:

Dimethyl-4-(tert-butylperoxy)-6-oxo-3,4,6,10b-tetrahydropyrido [2,1-a]isoindole-1,1(2H)-dicarboxylate (12b) (33 mg, 88 % yield): white solid, MS (ESI) m/z: 392 (M+1). 1 H-NMR: 7.85 (1H, d, J = 7.3), 7.54–7.46 (3H, m), 6.07 (1H, t, J = 2.8), 5.32 (1H, s), 3.88 (3H, s), 3.24 (3H, s), 2.49–2.00 (4H, m), 1.21 (9H, s). 13 C-NMR: 170.9, 167.7, 167.3, 143.4, 131.8, 131.5, 128.3, 124.4, 123.8, 80.9, 79.0, 57.3, 57.2, 53.1, 52.1, 27.5, 26.3 (3C), 23.8. Anal. Calcd. for C20 H25 NO7 : C, 61.37; H, 6.44; N, 3.58; O, 28.61. Found: C, 61.40; H, 6.46; N, 3.56.

Dimethyl-6-oxo-4-((2-phenylpropan-2-yl)peroxy)-3,4,6, 10b-tetrahydropyrido[2,1-a]isoindole-1,1(2H)dicarboxylate (12c) (34 mg, 78 % yield): white solid, MS (ESI) m/z: 454 (M+1). 1 H-NMR: 7.88 (1H, d, J = 6.5), 7.53–7.35 (5H, m), 7.13– 7.11 (3H, m), 6.05 (1H, d, J = 2.2), 4.76 (1H, s), 3.84 (3H, s), 3.21 (3H, s), 2.35–2.31 (1H, m), 2.11–2.01 (2H, m), 1.97– 1.91 (1H, m), 1.62 (3H, s), 1.49 83H, s). 13 C-NMR: 170.8, 167.7, 167.4, 144.9, 143,6, 131.8, 131.5, 128.2, 127.8 (2C), 127.0, 125.5 (2C), 124.3, 123.7, 83.1, 78.6, 57.1, 56.9, 53.0, 52.0, 27.3, 27.1, 25.5, 23.8. Anal. Calcd. for C25 H27 NO7 : C, 66.21; H, 6.00; N, 3.09; O, 24.70. Found: C, 66.23; H, 5.99; N, 3.10. Experimental procedure for one-pot synthesis of enamides D A solution of X–CH2 –Y (1.0 mmol) and o-CNC6 H4 CHO (1.0 mmol) in CH3 CN/TEABF4 (0.6 mL/0.08 mmol) was electrolyzed at the cathode compartment of a divided cell under galvanostatic conditions (Pt-anode and cathode; I = 20 mA; Q = 0.08 electrons/molecule of X–CH2 –Y). At the end of the electrolysis, the reaction was prolonged at r.t. under magnetic stirring until TLC disappearance of o-CNC6 H4 CHO; acrolein (1.2 mmol) was subsequently added. The mixture was kept under stirring upto complete the reaction (TLC disappearance of isoindolinone intermediate) and p-TsOH (0.1 mmol) was added. At the end of the reaction, the mixture was concentrated in vacuum and purified by flash chromatography. Dimethyl-6-oxo-6,10b-dihydropyrido[2,1-a]isoindole1,1(2H)-dicarboxylate (25 mg, 83 % yield): white solid, MS (ESI) m/z: 302 (M+1). 1 H-NMR: 7.88–7.85 (1H, m), 7.56–7.44 (3H, m), 7.11–7.08

(1H, m), 5.27–5.22 (1H, m), 5.09 (1H, s), 3.91 (3H, s), 3.51 (3H, s), 3.35 (3H, s), 3.06 (1H, dd, J1 = 17.4; J2 = 5.8), 2.76–2.69 (1H, m). 13 C-NMR: 170.8, 167.1, 165.1, 142.7, 132.1, 131.8, 128.6, 123.8, 123.2, 121.8, 106.0, 59.9, 56.3, 53.3, 52.4, 32.2. Anal. Calcd. for C16 H15 NO5 : C, 63.78; H, 5.02; N, 4.65; O, 26.55. Found: C, 63.81; H, 5.03; N, 4.67. Di-tert-butyl 6-oxo-6,10b-dihydropyrido [2,1-a]isoindole-1,1(2H)-dicarboxylate (33 mg, 85 % yield): white solid, MS (ESI) m/z: 386 (M+1). 7.84 (1H, d, J = 7.3), 7.66 (1H, d, J = 7.6), 7.54–7.44 (2H, m), 7.07 (1H, d, J = 7.9), 5.30–5.25 (1H, m), 5.07 (1H, s), 3.00 (1H, dd, J1 = 17.3; J2 = 5.7), 2.52 (1H, m), 1.53 (9H, s), 0.91 (9H, s). 13 C-NMR: 169.8, 165.4, 164.8, 143.6, 132.0, 131.8, 128.2, 124.6, 123.5, 121.3, 107.0, 1 H-NMR:

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Mol Divers

83.1, 81.7, 59.8, 57.5, 32.1, 27.9 (3C), 27.1 (3C). Anal. Calcd. for C22 H27 NO5 : C, 68.55; H, 7.06; N, 3.63; O, 20.75. Found: C, 68.58; H, 7.05; N, 3.67. Di-tert-butyl-4-((2-chlorobenzoyl)oxy)-3-hydroxy-6-oxo3,4,6,10b-tetrahydropyrido[2,1-a]isoindole-1,1(2H)dicarboxylate (13a) Enamide D (20 mg, 0.052 mmol), 2 mL of CH2 Cl2 , and 0.075 mmol of MCPBA were kept at 0 ◦ C under stirring for 3 h. At the end of the reaction, aq. sat. NaHCO3 (2 mL) was added and the mixture extracted twice with CH2 Cl2 (6 mL). The combined organic extracts were dried over Na2 SO4 , concentrated in vacuum and purified by flash chromatography. (23 mg, 80 % yield), white solid, MS (ESI) m/z: 582 (M+Na+ ). 1 H-NMR: 7.96–7.28 (9H, m), 5.34 (1H, s), 4.89– 4.87 (1H, m), 2.70 (1H, dd, J1 = 13.2; J2 = 4.9), 2.20 (1H, dd, J1 = 13.2; J2 = 11.5), 1.57 (9H, s), 0.93 (9H, s). 13 C-NMR: 169.0, 166.4, 166.1, 164.4, 143.0, 134.5, 133.4, 132.0, 131.2, 131.1, 129.8, 129.7, 128.6, 128.0, 126.2, 124.0, 83.2, 82.5, 73.9, 64.7, 58.9, 57.1, 34.5, 27.9, 27.1. Anal. Calcd. for C29 H32 ClNO8 : C, 62.42; H, 5.78; Cl, 6.35; N, 2.51; O, 22.94. Found: C, 62.45; H, 5.80; N, 2.49. Di-tert-butyl- 3,4-dihydroxy-6-oxo-3,4,6,10b-tetrahydropyrido [2,1-a]isoindole-1,1(2H)-dicarboxylate (14) A solution of 13a (28 mg, 0.05 mmol) and TEABF4 (11 mg, 0.05 mmol) in MeOH (0.25 mL) was electrolyzed at the cathode compartment of a divided cell under galvanostatic conditions (Pt-anode and -cathode; I = 10 mA; Q = 1 electrons/molecule of 13a). At the end of the electrolysis, the catholyte was concentrated in vacuum and the crude was purified by flash chromatography. 14 (21 mg, >98 % yield): white solid, MS (ESI) m/z: 420 (M+1). 1 H-NMR: 7.73 (1H, d, J = 7.3), 7.71 (1H, d, J = 7.5), 7.50–7.38 (2H, m), 5.90 (1H, d, J = 4.3), 5.27 (1H, s), 4.48–4.40 (1H, m), 2.55 (1H, dd, J1 = 13.1; J2 = 4.8), 2.10 (1H, dd, J1 = 13.1; J2 = 11.1), 1.54 (9H, s), 0.89 (9H, s). 13 C-NMR: 169.0, 167.7, 166.4, 143.3, 131.7, 131.5, 128.4, 126.2, 123.2, 82.7, 82.0, 71.3, 65.0, 58.9, 56.2, 34.5, 27.8 (3C), 27.1 (3C). Anal. Calcd. for C22 H29 NO7 : C, 62.99; H, 6.97; N, 3.34; O, 26.70. Found: C, 63.02; H, 7.00; N, 3.33 Di-tert-butyl- 3-((3-chlorobenzoyl)oxy)-4-hydroxy-6oxo-3,4,6,10b-tetrahydropyrido[2,1-a]isoindole-1,1(2H)dicarboxylate (13b) Enamide D (20 mg, 0.052 mmol), 2 mL of CH2 Cl2 , 0.075 mmol of K2 CO3 , and 0.075 mmol of MCPBA were kept at 0 ◦ C under stirring for 3 h. At the end of the reaction, aq. sat. NaHCO3 (2 mL) was added and the mixture extracted twice

123

with CH2 Cl2 (6 mL). The combined organic extracts were dried over Na2 SO4 , concentrated in vacuum and purified by flash chromatography. 13b (17 mg, 58 % yield) white solid, MS (ESI) m/z: 580 (M + Na+ ). 1 H-NMR: 8.08–7.37 (8H, m), 6.21 (1H, d, J = 4.0), 5.82–5.74 (1H, m), 5.39 (1H, s), 2.67 (1H, dd, J1 = 13.0; J2 = 5.0), 2.67 (1H, dd, J1 = 13.0; J2 = 13.0), 1.54 (9H, s), 0.94 (9H, s). 13 C-NMR: 170.0, 167.6, 167.5, 164.4, 143.2, 134.0, 133.3, 131.9, 131.3, 131.1, 129.8, 129.7, 128.6, 128.0, 125.0, 124.2, 83.0, 82.2, 71.5, 68.5, 58.8, 57.0, 33.7, 27.9 (3C), 27.1 (3C). Anal. Calcd. for C29 H32 ClNO8 : C, 62.42; H, 5.78; Cl, 6.35; N, 2.51; O, 22.94. Found: C, 62.46; H, 5.78; N, 2.50

Di-tert-butyl- 4-((3-chlorobenzoyl)oxy)-3,6-dioxo3,4,6,10b-tetrahydropyrido[2,1-a]isoindole-1,1(2H)dicarboxylate (15a) EnamideD (23 mg, 0.06 mmol) was dissolved in CH2 Cl2 (2 mL) and 0.075 mmol of MCPBA were added. The mixture was kept at 0 ◦ C under stirring for 3 h, then molecular sieves and PDC (1.5 eq.) were added. The reaction was monitored by TLC. At the end of the reaction, MeOH (1 mL) was added, the mixture was filtered, concentrated in vacuum and purified by flash chromatography. 15a (23 mg, 70 % yield): paleyellow solid, MS (ESI) m/z: 577.96 (M + Na+ ). 1 H-NMR: 8.08–7.36 (8H, m), 6.36 (1H, s), 5.81 (1H, s), 3.24 (2H, s), 1.54 (9H, s), 0.95 (9H, s). 13 C-NMR: 196,3, 168.3, 167.6, 166.9, 164.9, 143.0, 134.6, 133.8, 133.6, 132.8, 130.8, 130.1, 129.8, 129.1, 128.3, 126.4, 124.0, 83.5, 83.4, 75.4, 60.4, 59.7, 43.5, 27.8 (3C), 27.0 (3C). Anal. Calcd. for C29 H30 ClNO8 : C, 62.65; H, 5.44; Cl, 6.38; N, 2.52; O, 23.02. Found: C, 62.69; H, 5.45; N, 2.50

Di-tert-butyl 3-((3-chlorobenzoyl)oxy)-4,6-dioxo-3,4,6,10btetrahydropyrido[2,1-a]isoindole-1,1(2H)-dicarboxylate (15b) 13b (28 mg, 0.05 mmol) in CH2 Cl2 (2 mL), molecular sieves and PDC (1.5 eq.) were kept at 0 ◦ C under stirring for 3 h. The reaction was monitored by TLC. At the end of the reaction, MeOH (1 mL) was added, the mixture was filtered, concentrated in vacuum and purified by flash chromatography. 15b (24 mg, 86 % yield): pale- yellow solid, MS (ESI) m/z: 556 (M+1). 1 H-NMR: 8.02–7.37 (8H, m), 5.88 (1H, s), 5.80–5.74 (1H, m), 3.05 (1H, dd, J1 = 14.1; J2 = 6.7), 2.63 (1H, dd, J1 = 14.1; J2 = 7.5), 1.51 (9H, s), 0.97 (9H, s). 13 C-NMR: 168.5, 165.9, 165.8, 164.7, 164.2, 142.2, 134.7, 133.9, 133.7, 130.6, 130.1, 130.0, 129.9, 129.3, 128.1, 125.8, 125.1, 84.0, 83.3, 71.0, 60.9, 58.7, 53.4, 35.5, 27.8, 27.2. Anal. Calcd. for C29 H30 ClNO8 : C, 62.65; H, 5.44; Cl, 6.38; N, 2.52; O, 23.02. Found: C, 62.67; H, 5.46; N, 2.52.

Mol Divers Acknowledgments Financial support from the Ministero dell’ Università e della Ricerca (MIUR) (FARB 2011) is gratefully acknowledged.

18.

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chemical methods for the synthesis and the molecular diversifying of isoindolinone-based heterocyclic scaffolds.

By means of C-H acids activation on Pt-cathode, an electrochemically initiated strategy aimed to developing a diversity-oriented synthesis based on th...
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