5-Annulation of Ketoimines: TFA-Catalyzed Construction of

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Article Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX

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5‑Annulation of Ketoimines: TFA-Catalyzed Construction of Isoindolinone-3-carboxylates and Development of Photophysical Properties Anirban Kayet, Sk Ajarul, Sima Paul, and Dilip K. Maiti* Department of Chemistry, University of Calcutta, University College of Science, 92, A. P. C. Road, Kolkata 700009, India

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S Supporting Information *

ABSTRACT: Herein we have demonstrated the first report on 5-annulation of ketoimines to valuable isoindolinone-3carboxylates. Instead of commonly used aldimine substrates, relatively less reactive ketoimines are employed for developing a TFA catalyzed organoreductive cyclization to furnish a variety of isoindolinones in excellent yield and reaction rate under mild reaction conditions. This is a metal-free event, which proceeds through a one pot ketoimine formation, hydride transfer from an organic reductant 2-(naphthalen-2-yl)-2,3-dihydrobenzo[d]thiazole, and followed by five member cyclization sequences through TFA-activation of imine and ester groups. Studies on ESI-MS kinetics, leaving group aptitude, and control experiments led us to propose the mechanistic pathway of the new ketoimine-lactamization reaction. We have shown the synthetic utility of the emerging synthons through easy transformation of isoindolinones to different synthetic analogues. We investigated photophysical properties of the small molecules for their futuristic application as a pharmaceutical and materials, and the heterocycles displayed brilliant fluorescence activity.

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INTRODUCTION The motivation of a researcher in the synthetic chemistry field is to devise an effective strategy for a challenging reaction using uncommon synthons to desirable compounds with installation of extra functionalities and selectivities. For instance, commonly used aldimine synthons1,2 may be replaced by ketoimines3 to achieve the goal of reckoning extra substituents, functionalities, and/or stereogenic centers. However, ketoimines are in general difficult to synthesize, purify, and store, have E/Z isomers, are relatively unreactive in nature, and suffer from steric congestion during nucleophilic addition.4 Contrary to the wide use of aldimines, ketoimines have found limited application as synthons, particularly in the metal-free cyclization5 and 5annulation.6 In particular, aldimines are frequently used for syntheses of valuable 3-substituted isoindolinones2 employing metal Lewis acids such as Rh(I), Cu(I), Cu(II), Zn(II), and In(III) for the lactamization and C3-alkylation or multistep reactions. It can easily be performed through a sustainable direct approach involving strongly coordinated transition state of ketoimines (TS, Scheme 1) with a Brønsted acid catalyst (R4CX2H). © XXXX American Chemical Society

The isoindolinone-3-carboxylates and carboxamide analogues were found as therapeutic inhibitors of microsomal triglyceride transfer protein and apolipoprotein B secretion (i, Figure 1),7 state-dependent blockers of voltage-gated sodium channel NaV1.7 and medicine for pain disorder (ii),8 function modulator for muscarin and serotonin receptors, aldose reductase inhibitor for diabetics (iii), antihyperglycemic, and anxiolytics,9 blood pressure regulatory inhibitors of phosphatidylinositol-3-kinase, medicine for cardiac arrhythmias, inhibitors for HIV-reverse transcriptase and renin.10 Thus, isoindolinone-3-carboxylates are emerged as attractive synthons for enantioselective Michael reaction,11 spirolactonization,12 hydrogenated octahydroisoindole core structure,13 and large scale synthesis of pharmaceuticals7 of Pfizer. The widely used synthons are most frequently synthesized using the methods as described by Massa et al. and Rammah et al. through coupling of amines with hazardous αbromohomophthalates.11,12 The other important strategies were reported involving precursor phthalimide derivatives, NH3/ CN− and CO2 (via lithiation),14 carbon monoxide fixation Received: April 25, 2018

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DOI: 10.1021/acs.joc.8b01049 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry Scheme 1. Organocatalyzed Annulation of Ketoimines to Isoindolinones

Table 1. Initial Study for Developing 5-Annulation of Ketoiminea

Figure 1. Bioactive isoindolinone-3-carboxylate and analogues.

involving orthopalladation of aryl glycinate13b and treatment of phthalonic acid with hydrazine and reduction with zinc.15 The reported strategies suffered from severe limitations, e.g., most frequently used coupling reaction of α-bromohomophthalates with amines restrains because it requires special tuning depending on the nature of amines.11c On the other hand, addition of ammonia and cyanide to phthalaldehydic acid and treatment of phthalonic acid with hydrazine limit the scope of the reactions because of the use of toxic reagents.14a,15 Again the requirement of metal catalysts13b,15 may suffer from severe limitations due to the presence of traces of toxic metals in the target compound owing to the fact that residual metal catalyst causes interference during photophysical and optoelectronic studies. Thus, the broad spectrum of application has triggered a demand for development of a metal-free, milder, simpler, rapid, high yielding, and environment friendly route to access the widely used synthons. The aforementioned criteria can be addressed according to the designed 5-annulation of ketoimines (Scheme 1) using a suitable organocatalyst16 and organoreductant.17,18

entry

6 (mmol)

solvent

catalyst (mol %)

temp (°C)

time (h)

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

6a (1.2) 6a (1.2) 6b (1.2) 6c (1.2) 6d (1.2) 6e (1.2) 6f (1.2) 6g (1.2) 6h (1.0) 6h (1.0) 6g (1.2) 6g (1.2) 6g (1.2) 6g (1.2) 6g (1.2) 6g (1.2) 6g (1.2) 6g (1.2) 6g (1.2) 6g (1.2) 6g (1.2) 6g (1.2) 6g (1.2) 6g (1.2) 6g (1.2) 6g (1.2) 6g (1.2) 6g (1.2) 6g (1.0) 6g (1.2)

DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM EDC THF Et2O CH3CN DMF C6H6 PhMe EtOH DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM

TFA (10) TFA (10) TFA (10) TFA (10) TFA(10) TFA (10) TFA (10) TFA (10) TFA (10) TFA (10) TFA (10) TFA (10) TFA (10) TFA (10) TFA (10) TFA (10) TFA (10) TFA (10) TFA (10) AcOH (10) PTSA (10) TfOH (10) BAe (10) NBAf (10) CSAg (10) HCl (10) TFA (20) TFA (05) TFA (10) TFA (10)

25 40 25 25 25 25 25 25 25 50 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25

24 24 2.0 2.0 4.0 3.0 2.0 0.75 24 24 1.5 2.0 5 4.5 5 5 3 3 7 4 24 2 4 24 2 24 0.75 1.5 1 1

NRc 20d 70 72 50d 60d 80 93 NRc NRc 82 80 40d 30d 40d 45d 55d 57d 40d 60 35d 65 25 32 45 NRc 75 80 80 92h

a Reactions were carried out using precursor (1a, 1 mmol), PMP amine (3a, 1.1 mmol) in the presence of 6 (1.2 mmol) and Bronsted acids (0.1 mmol). bYield of the isolated product after column purification. cNo reaction. dUnreacted ketoimine was recovered. e Benzoic acid. f4-Nitrobenzoic acid. gCamphor sulfonic acid. hGramscale synthesis.

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RESULTS AND DISCUSSION To achieve the goal, our investigation was initiated through trifluoroacetic acid (TFA)-catalyzed 5-annulation of in situ generated ketoimine (4a) from 1a with 4-methoxy phenylamine 3a under organoreductive mild reaction conditions for easy access to 3-oxo-isoindoline-1-carboxylate (5a, Table 1). It was noticed that a mixture of organoreductant17 (6a, 1.2 mmol) and TFA (10 mol %) could not afford desired isoindolinone (5a) even after prolonged stirring in dichloromethane (DCM) at ambient temperature (entry 1). The desired product was obtained in low yield (20%) on refluxing the reaction content for 24 h (entry 2). Gratifyingly on changing Hantzsch ester (6a) to thiazoline-based reducing agents17g,18 (6b−g, 1.2 mmol), the yield was improved (entries 3−8) from moderate (50%, Ar = 4NO2−C6H4, entry 5) to excellent (93%, Ar = naphthyl, entry 8)

depending on their reducing ability. However, commonly used reducing agent 1,2,3,4-tetrahydronaphthalene (6h) was not effective even at elevated temperature (entries 9, 10). An extensive study using aprotic polar (entries 12−16), nonpolar (entries 17, 18), and protic solvent (entry 19) revealed that DCM is the best medium for the 5- annulation with excellent yield (93%, entry 8). A brief survey on the choice of Brønsted acid catalyst (0−65% yield, entries 20−25) showed that TFA (93%, entry 8) is the best for the formation of the isoindolinone 5a under the reaction conditions. Increasing concentration of TFA (20 mol %) showed negative effect in this reaction by lowering the yield of 5a (75%, entry 27), which may occur due to the decomposition of ketoimine (4a) to some extent, where as B

DOI: 10.1021/acs.joc.8b01049 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry lower concentration of TFA (5 mol %, entry 28) slowed down the reaction rate and reduced yield (80%). The yield was significantly reduced (80%, entry 29) on using lesser amount of the reductant (1.0 mmol). A gram-scale synthesis of 5a under the optimized reaction conditions was also verified to afford the desired product in 92% (entry 30), which validated the strategy for the large-scale synthesis of the widely used synthons. Next we examined generality of this strategy using a wide range of aromatic amines (3b−q, Scheme 2) under the

Scheme 3. Scope of Ketoimines in the 5-Annulation Process

Scheme 2. Scope of Aromatic Amines in the 5-Annulation of Ketoimine

the substrate bearing highly electron withdrawing group directly attached to the carbon of ketoimine. To our delight, following the synthetic strategy,20 precursor 2 also served as a good substrate for smooth construction of isoindolinone 10 in 93% yields via the in situ generated ketoimine 8. On the basis of the results, our control experiments, and literature reports led us to delineate a plausible mechanistic cycle (Scheme 4). It is expected to pass through reduction of the ketoimine (I) via TFA mediated activation of the imine leading to transfer of a hydride from 2-naphthylbenzothiazoline18a (III) affording the corresponding amino ester (VI) with knock off 2naphthyl-benzothiazole (V), which is confirmed through its isolation and characterization. The intermediate VI is expected to undergo TFA-mediated 5-annulation reaction through activation of ester by TFA furnishing the desired isoindolinone (5, 9, 10) with release of methanol and regeneration of TFA catalyst for the next organocatalytic cycle. However, formation of isoindolinones through the possible transition state TS (R4 = CF3, X = O; Scheme 1) may not be avoided. Our ESI-MS kinetics data from an aliquot of the ongoing reaction showed the presence of symbolic mass peaks for the intermediates I, V and VI as well as the isoindolinone 5a. We have also studied influence of leaving group aptitude of the ester functionality to gain mechanistic insight. Interestingly our control experiments

optimized reaction conditions (entry 8, Table 1). Aniline (3b) and the phenyl ring bearing electronically poor (NO2, F, Cl, Br, I and OCF3) and electron rich (Me, Et, isopropyl, methoxy and dioxomethylene) anilines (3c−h and 3i−o) worked well in this reductive 5-annulation furnishing the isoindolinones 5b−o in excellent yield (90−94%). 4-Hydroxy aniline (3p) and pyridylamine (3q) were also well tolerated under the mild conditions affording 5p and 5q in a synthetically viable yield (90−93%). Although several aromatic amines worked well in this 5annulation reaction, but unfortunately, aliphatic amines failed to work in this process. We have also explored the scope of the reaction using a variety substituted methyl benzoates (1b−m, Scheme 3) synthesized newly according to the literature procedure.19 The reaction of the substrates 1b−m and 3k resulted in situ generation of the ketoimines 7a−k which worked well under the optimized reaction conditions to afford the corresponding isoindolinones 9a−k respectively in excellent yield (90−94%) within 1 h. We investigated viability of the reductive cyclization reaction with C

DOI: 10.1021/acs.joc.8b01049 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry

the corresponding alcohol (13)21 with 96% yield (path a) which on treatment with CAN in acetonitrile−water furnished the PMP deprotected alcohol (14)22 in 50% yield (path b). In addition the alcohol 14 was achieved in 51% yield over two steps from 5a (path c). Again, compound 5a on treatment with NaOH in THF−water produced the acid derivative (15) in good yield (80%) (path d). On the other hand, nitro group of the isoindolinone 9c was reduced to amino group on treatment with (Ni(OAc)2·4H2O in ethanol with 95% yield (path e). Development of innovative photophysical properties of new molecules, especially the brilliant fluorescence of organic compounds is an active research area because it has practical application in clinical biochemistry, medicinal and analytical chemistry, environmental science, and sensing research and technology.23 With this application in our mind and synthetic flexibility of isoindolinone-3-carboxylates, we have investigated absorption and emission properties of six compounds, 5a, 5b, 5q and 9f, 9i, 9k in nonpolar, polar and polar protic solvents (hexane, DCM, DMSO and MeOH), which will be helpful for the futuristic application of the heterocycles and their analogues in medicinal and material researches. Our study revealed that compound 5q having highest absorption maxima (λmax) at 333 nm in DMSO and exhibited the highest quantum yield in DMSO compared to the rest of the isoindolinones (Supporting Information). A sharp change in emission maxima for 5a, 5b and 9i was found to be bathochromic shifted by 35 nm upon changing the solvent from nonpolar hexane to strongly polar DMSO, and the bathochromic shift was even larger for 5q and 9k (Supporting Information). Surprisingly strong fluorescence intensity at 500 nm is observed for 9f in DMSO (Figure 2 and

Scheme 4. Plausible Mechanism and Control Experiments

with the in situ generated ketimines (12a and 12b) obtained by the reaction of synthesized ketoesters (11a and 11b) and 3,4dimethoxy aniline (3l), showed significantly enhanced reaction rate (15 or 20 min) with respect to corresponding methyl ester substrate (30 min, 4a) to obtain isoindolinone 5a. It is expected that release of steric strain in the transition state favored the reaction rates. We have also shown the synthetic utility of the emerging synthons isoindolinones through its easy transformation to different synthetic analogues (Scheme 5). For instance isoindolinone 5a on treatment with NaBH4 in ethanol afforded

Figure 2. Photophysical properties of 9f. (a) Absorption and (b) fluorescence spectra of 9f recorded at concentration 2.0 × 10−4 M in different solvents.

Table 2). This interesting property is attributed due to typical structural pattern and extended conjugation between the phenyl ring and the isoindolinone-3-carboxylate moiety.

Scheme 5. Synthetic Elaboration to Some Advanced Intermediates

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CONCLUSIONS In conclusion, we have successfully demonstrated the first report of 5-annulation of ketoimines to functionalized isoindolinone-3Table 2. Optical Data of 9f solvent

λabs (nm)

ε (105 M−1 cm−1)

λem (nm)

Φa

hexane DCM MeOH DMSO

295 284, 300 294 308

1.87 7.60 7.60 5.89

456 460 459 500

0.21 0.69 0.15 0.46

Φ measurements were performed using anthracene in ethanol as standard [Φ = 0.27] (error ∼10%).24 a

D

DOI: 10.1021/acs.joc.8b01049 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry

acetonitrile (6 mL) and cooled to 0 °C. Cerric ammonium nitrate (CAN) (1.488 mmol) dissolved in 2 mL water was added to it, and the reaction mixture was stirred at 0 °C for 10 min. After complete consumption of 13, the reaction mixture was quenched with NaHCO3 solution and extracted with EtOAc. The organic layer ware dried over anhydrous Na2SO4 and evaporated to dryness to get a residue that was purified over silica gel column chromatography. Procedure for Synthesis of 2-(4-Methoxyphenyl)-3-oxoisoindoline-1-carboxylic Acid (15). To a well stirred solution of compound 5a (100 mg, 0.322 mmol) in THF (5 mL), 1 M NaOH solution (2 mL) was added at room temperature, and the reaction was continued for 2 h. THF was removed, and the residue was extracted with water and EtOAc. The aqueous layer was acidified with cold HCl and extracted with EtOAc (3 × 15 mL). The organic layer was evaporated to dryness under reduced pressure to get a pure compound 15, which did not need further purification. Procedure for Synthesis of Ethyl 5-amino-2-(3,4-dimethoxyphenyl)-3-oxoisoindoline-1-carboxylate (9d). Compound 9c (100 mg, 0.26 mmol) was dissolved in ethanol, and nickel acetate tetrahydrate [Ni(OAc)2·4H2O] (0.39 mmol) was added at 0 °C. After 5 min the reaction mixture was allowed to stir at room temperature for additional 2 h. Ethanol was removed under reduced pressure, water was added and extracted with EtOAc. The organic layer was dried over Na2SO4 and evaporated to dryness to get a crude residue, which was washed with hexane to remove low polar impurity. On complete dryness compound 9d was achieved in 95% yield without further purification. Ethyl 2-(4-methoxyphenyl)-3-oxoisoindoline-1-carboxylate (5a). Yield of 5a is (290 mg, 93%) as white solid. Rf = 0.2 (15% EtOAc in hexanes, TLC); mp 118−119 °C; 1H NMR (300 MHz, CDCl3) δ 1.11 (t, 3H, J = 7.2 Hz), 3.77 (s, 3H), 4.01−4.19 (m, 2H), 5.63 (s, 1H), 6.88−6.92 (m, 2H), 7.49−7.87 (m, 5H), 7.89 (d, 1H, J = 1.50 Hz); 13C NMR (75 MHz, CDCl3) δ 14.0, 55.3, 62.1, 64.1, 114.3, 122.3, 123.8, 124.3, 129.4, 130.8, 132.0, 132.2, 138.6, 157.3, 167.3, 168.0; FT-IR (film) υmax 1748, 1702, 1512, 1472, 1371, 1247, 1178, 1034, 737 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C18H18NO4 312.1236, found 312.1260. Ethyl 3-oxo-2-phenylisoindoline-1-carboxylate (5b). Yield of 5b is (260 mg, 93%) as yellowish solid. Rf = 0.3 (20% EtOAc in hexanes, TLC); mp 120−121 °C; 1H NMR (300 MHz, CDCl3) δ 1.05 (t, 3H, J = 6.9 Hz), 3.95−4.18 (m, 2H), 5.67 (s, 1H), 7.11−7.18 (m, 1H), 7.34 (t, 2H, J = 7.8 Hz), 7.46−7.63 (m, 5H), 7.87 (d, 1H, J = 7.5 Hz); 13C NMR (75 MHz, CDCl3) δ 13.9, 62.2, 63.6, 121.1, 122.3, 124.4, 125.2, 129.1, 129.5, 132.1, 132.5, 138.1, 138.5, 167.3, 168.0; FT-IR (film) υmax 1750, 1709, 1521, 1442, 1351, 1254, 1168, 1029, 717 cm−1; HRMS (ESITOF) m/z [M + H]+ calcd for C17H16NO3 282.1130, found 282.1105. Ethyl 2-(4-nitrophenyl)-3-oxoisoindoline-1-carboxylate (5c). Yield of 5c is (293 mg, 90%) as white solid. Rf = 0.2 (20% EtOAc in hexanes, TLC); mp 128−130 °C; 1H NMR (300 MHz, CDCl3) δ 1.16 (t, 3H, J = 7.2 Hz), 4.09−4.27 (m, 2H), 5.88 (s, 1H), 7.25−7.30 (m, 1H), 7.46 (t, 2H, J = 8.1 Hz), 7.67 (d, 2H. J = 7.8 Hz), 7.86 (d, 1H, J = 8.4 Hz), 8.50−8.53 (m, 1H), 8.77 (d, 1H, J = 1.5 Hz); 13C NMR (75 MHz, CDCl3) δ 13.9, 62.9, 63.8, 120.0, 121.4, 123.8, 126.0, 127.4, 129.4, 133.9, 137.3, 143.9, 149.4, 165.0, 166.7; FT-IR (film) υmax 1757, 1695, 1532, 1356, 1211, 1081, 999, 752 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C17H15N2O5 327.0981, found 327.1004. Ethyl 2-(3-chloro-4-fluorophenyl)-3-oxoisoindoline-1-carboxylate (5d). Yield of 5d is (300 mg, 90%) as white solid. Rf = 0.2 (20% EtOAc in hexanes, TLC); mp 140−142 °C; 1H NMR (300 MHz, CDCl3) δ 1.15 (t, 3H, J = 7.2 Hz), 4.07−4.26 (m, 2H), 5.64 (s, 1H), 6.54 (t, 1H, J = 7.5 Hz), 6.67 (d, 1H, J = 8.4 Hz), 7.09−7.23 (m, 3H), 7.45−7.62 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 14.0, 62.5, 63.6, 115.2, 116.8 (d, J = 22.0 Hz), 118.2, 121.0 (d, J = 6.0 Hz), 122.5, 123.8, 124.6, 131.3 (d, J = 235.0 Hz), 131.5 (d, J = 9.0 Hz), 136.8, 138.4, 148.6, 167.3, 167.6; FT-IR (film) υmax 1756, 1659, 1533, 1368, 1198, 1087, 999, 748 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C17H14ClFNO3 334.0646, found 334.0657. Ethyl 2-(4-chlorophenyl)-3-oxoisoindoline-1-carboxylate (5e). Yield of 5e is (287 mg, 92%) as white solid. Rf = 0.3 (20% EtOAc in hexanes, TLC); mp 120−122 °C; 1H NMR (300 MHz, CDCl3) δ 1.12

carboxylates under organoreductive TFA catalysis. We believe that the high yielding cyclization reaction, mechanistic study employing control experiments, leaving aptitude of leaving group, ESI-MS kinetics, TFA catalyzed activation of ketoimine and ester for the new organoreductive annulation, easy access to a wide range of functionalized isoindolinone-3-carboxylates, synthetic elaboration to some advanced intermediates, and high fluorescence properties of the new compounds might find application in the chemical and medicinal sciences.

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EXPERIMENTAL SECTION

General Information. Unless otherwise stated, reactions were performed in oven-dried glassware fitted with rubber septa and were stirred with Teflon-coated magnetic stirring bars. Liquid reagents and solvents were transferred via syringe using standard Schlenk techniques. Tetrahydrofuran (THF), diethyl ether (Et2O), benzene and toluene were distilled over sodium/benzophenone ketyl. Acetonitrile, dichloromethane (DCM) and 1,2-ethylene dichloride (EDC) were distilled over calcium hydride. All other solvents and reagents were used as received unless otherwise noted. Reaction temperatures above 25 °C refer to oil bath temperature. Thin layer chromatography was performed using silica gel 60 F-254 precoated plates (0.25 mm) and visualized by UV irradiation, anisaldehyde stain and other stains. Silica gel of particle size 100−200 mesh was used for column chromatography. Melting points were recorded on a digital melting point apparatus from Jyoti Scientific (AN ISO 9001:2000) and are uncorrected. 1H, 13C and DEPT135 NMR spectra were recorded with 300, 400 and 500 MHz spectrometers with 13C operating frequencies of 75, 100 and 125 MHz, respectively. Chemical shifts (δ) are reported in ppm relative to the residual solvent CDCl3 signal (δ = 7.24 for 1H NMR and δ = 77.0 for 13C NMR), DMSO-d6 signal (δ = 2.47 for 1H NMR and δ = 39.4−40.6 for 13C NMR). Data for 1H NMR spectra are reported as follows: chemical shift (multiplicity, number of hydrogen and coupling constants). Abbreviations are as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad). IR spectra were recorded on a FT-IR system (Spectrum BX) and are reported in frequency of absorption (cm−1). Only selected IR absorbance is reported. High-resolution mass spectrometry (HRMS) data was recorded on Q-ToF-micro quadruple mass spectrophotometer using acetonitrile as solvent. General Procedure for the Synthesis of Isoindolinone-3carboxylates. To a well stirred solution of compound 1a (1 mmol) in benzene was added aromatic and heteroaromatic amines 3a−q (1.1 mmol), para-toluene sulfonic acid (PTSA) (0.1 mmol), and the reaction mixture was refluxed for overnight. After complete consumption of starting material, the reaction mixture was cooled, and benzene was removed under reduced pressure to get ketoimines 4a−q, which were used for the next step without further purification. The crude residue was dissolved in dry DCM, and thiazoline 6g (1.2 mmol) and trifluoroacetic acid (TFA, 0.1 mmol) were added to it. The reaction mixture was stirred at room temperature under inert condition for appropriate time (completion of reaction indicated by TLC). After completion of the reaction, solvent was removed, and the crude residue was purified over silica gel column chromatography to get pure isoindolinones 5a−q in 90−94% yields. Synthesis of 9a−k and 10 was performed by the same procedure through in situ generated ketoimines 7a−k and 8. Procedure for Synthesis of 3-(Hydroxymethyl)-2-(4methoxyphenyl)isoindolin-1-one (13). To a well stirred solution of 5a (100 mg, 0.322 mmol) in ethanol (4 mL) sodiumborohydride (NaBH4) (0.644 mmol) was added at 0 °C. The ice bath was removed after 5 min, and the reaction mixture was allowed to stir at room temperature for 4 h. After completion of the reaction, the solvent was removed under reduced pressure and extracted with EtOAc. It was washed with aqueous NH4Cl solution and water. The organic layer was dried over Na2SO4 and evaporated to dryness to get a residue. The residue was chromatographed over silica gel to get pure 13. Procedure for Synthesis of 3-(Hydroxymethyl)isoindolin-1one (14). Compound 13 (100 mg, 0.372 mmol) was dissolved in E

DOI: 10.1021/acs.joc.8b01049 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry (t, 3H, J = 7.2 Hz), 4.04−4.21 (m, 2H), 5.68 (s, 1H), 7.33 (d, 2H, J = 8.7 Hz), 7.49−7.63 (m, 5H), 7.87 (d, 1H, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 13.8, 29.5, 52.6, 62.3, 63.3, 122.0, 122.3, 124.3, 128.8, 129.5, 130.2, 131.6, 132.7, 136.6, 138.2, 167.2, 167.6; FT-IR (film) υmax 1767, 1708, 1531, 1458, 1324, 1217, 1164, 1024, 718 cm−1; HRMS (ESITOF) m/z [M + H]+ calcd for C17H15ClNO3 316.0740, found 316.0713. Ethyl 2-(4-bromophenyl)-3-oxoisoindoline-1-carboxylate (5f). Yield of 5f is (330 mg, 92%) as white solid. Rf = 0.3 (20% EtOAc in hexanes, TLC); mp 118−119 °C; 1H NMR (300 MHz, CDCl3) δ 1.07 (t, 3H, J = 7.2 Hz), 3.96−4.18 (m, 2H), 5.62 (s,1H), 7.32−7.61 (m, 7H), 7.83 (d, 1H, J = 7.5 Hz); 13C NMR (75 MHz, CDCl3) δ 13.9, 62.4, 63.3, 118.1, 122.3, 122.4, 124.5, 129.6, 131.7, 132.1, 132.7, 137.2, 138.3, 167.2, 167.7; FT-IR (film) υmax 1757, 1705, 1527, 1498, 1357, 1237, 1198, 1008, 729 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C17H15BrNO3 360.0235, found 360.0230. Ethyl 2-(4-iodophenyl)-3-oxoisoindoline-1-carboxylate (5g). Yield of 5g is (386 mg, 92%) as light yellowish solid. Rf = 0.3 (20% EtOAc in hexanes, TLC); mp 115−116 °C; 1H NMR (300 MHz, CDCl3) δ 1.20 (t, 3H, J = 7.2 Hz), 4.11−4.30 (m, 2H), 5.74 (s, 1H), 7.53−7.68 (m, 5H), 7.86−7.96 (m, 2H), 8.06 (d, 1H, J = 2.7 Hz); 13C NMR (75 MHz, CDCl3) δ 13.9, 62.7, 63.2, 119.4, 119.5, 122.5, 124.6, 124.7, 129.9, 131.3, 132.2, 133.2, 137.1, 138.2, 167.4; FT-IR (film) υmax 1763, 1701, 1538, 1428, 1314, 1219, 1134, 1014, 723 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C17H15INO3 408.0097, found 408.0094. Ethyl 3-oxo-2-(4-(trifluoromethoxy)phenyl)isoindoline-1-carboxylate (5h). Yield of 5h is (336 mg, 93%) as white solid. Rf = 0.2 (15% EtOAc in hexanes, TLC); mp 122−124 °C; 1H NMR (300 MHz, CDCl3) δ 1.10 (t, 3H, J = 7.2 Hz), 4.03−4.22 (m, 2H), 5.69 (s, 1H), 7.23 (d, 2H, J = 8.1 Hz), 7.51−7.67 (m, 3H), 7.69 (d, 2H, J = 6.9 Hz), 7.89 (d, 1H, J = 6.9 Hz); 13C NMR (75 MHz, CDCl3) δ 13.9, 62.5, 63.6, 121.8, 122.3, 122.5, 124.6, 129.8, 131.7, 132.9, 136.8, 138.4, 146.1, 167.4, 167.8; FT-IR (film) υmax 1767, 1699, 1528, 1413, 1334, 1217, 1154, 1035, 733 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C18H15F3NO4 366.0953, found 366.0975. Ethyl 2-(4-ethylphenyl)-3-oxoisoindoline-1-carboxylate (5i). Yield of 5i is (286 mg, 93%) as white solid. Rf = 0.3 (20% EtOAc in hexanes, TLC); mp 119−120 °C; 1H NMR (300 MHz, CDCl3) δ 1.09 (t, 3H, J = 7.2 Hz), 1.18 (t, 3H, J = 7.5 Hz), 2.59 (q, 2H, J = 7.5 Hz), 4.00−4.18 (m, 2H), 5.67 (s, 1H), 7.19 (d, 2H, J = 8.4 Hz), 7.47−7.57 (m, 5H), 7.87 (d, 1H, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 13.8, 15.4, 28.2, 62.1, 63.7, 121.4, 122.2, 124.3, 128.4, 129.4, 132.1, 132.3, 135.5, 138.5, 141.3, 167.2, 168.0; FT-IR (film) υmax 1751, 1702, 1518, 1469, 1360, 1293, 1178, 1017, 729 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H20NO3 310.1443, found 310.1413. Ethyl 2-(4-isopropylphenyl)-3-oxoisoindoline-1-carboxylate (5j). Yield of 5j is (300 mg, 94%) as colorless gum. Rf = 0.3 (20% EtOAc in hexanes, TLC); 1H NMR (300 MHz, CDCl3) δ 1.10 (t, 3H, J = 7.2 Hz), 1.12 (d, 6H, J = 6.9 Hz), 2.85−2.90 (m,1H), 4.02−4.20 (m, 2H), 5.67 (s, 1H), 7.23 (d, 2H, J = 8.7 Hz), 7.50−7.59 (m, 5H), 7.90 (d, 1H, J = 6.9 Hz); 13C NMR (75 MHz, CDCl3) δ 13.9, 23.9, 33.6, 62.1, 63.8, 121.5, 122.3, 124.4, 127.1, 129.5, 132.2, 132.3, 135.6, 138.6, 146.0, 167.3, 168.1; FT-IR (film) υmax 1752, 1700, 1528, 1448, 1365, 1289, 1168, 1016, 719 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H22NO3 324.1600, found 324.1628. Ethyl 2-(3,4-dimethylphenyl)-3-oxoisoindoline-1-carboxylate (5k). Yield of 5k is (290 mg, 94%) as brownish gum. Rf = 0.3 (20% EtOAc in hexanes, TLC); 1H NMR (300 MHz, CDCl3) δ 1.24 (t, 3H, J = 7.2 Hz), 2.32 (s, 3H), 2.37 (s,3H), 4.15−4.31 (m, 2H), 5.78 (s, 1H), 7.24 (d, 1H, J = 8.1 Hz), 7.41 (d, 1H, J = 8.1 Hz), 7.60−7.70 (m, 4H), 8.00 (d, 1H, J = 7.5 Hz); 13C NMR (75 MHz, CDCl3) δ 13.8, 19.1, 19.9, 62.0, 63.7, 118.9, 122.2, 122.9, 124.2, 129.3, 130., 132.1, 132.2, 133.8, 135.5, 137.3, 138.5, 167.2, 168.0; FT-IR (film) υmax 1748, 1703, 1609, 1511, 1364, 1176, 1029, 730 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H20NO3 310.1443, found 310.1439. Ethyl 2-(3,4-dimethoxyphenyl)-3-oxoisoindoline-1-carboxylate (5l). Yield of 5l is (320 mg, 94%) as white solid. Rf = 0.2 (25% EtOAc in hexanes, TLC); mp 124−126 °C; 1H NMR (300 MHz, CDCl3) δ 1.11 (t, 3H, J = 7.2 Hz), 3.82 (s, 3H), 3.87 (s, 3H), 4.02−4.19

(m, 2H), 5.64 (s, 1H), 6.80−6.88 (m, 2H), 7.50−7.57 (m, 4H), 7.86 (d, 1H, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 14.0, 55.9, 56.0, 62.2, 64.2, 106.8, 11.2, 113.3, 122.3, 124.3, 129.6, 131.4, 132.1, 132.5, 138.6, 146.8, 149.1, 167.5, 168.1; FT-IR (film) υmax 1749, 1697, 1521, 1466, 1386, 1247, 1178, 1023, 735 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H20NO5 342.1342, found 342.1335. Ethyl 2-(2,4-dimethoxyphenyl)-3-oxoisoindoline-1-carboxylate (5m). Yield of 5m is (346 mg, 90%) as white solid. Rf = 0.2 (25% EtOAc in hexanes, TLC); mp 123−124 °C; 1H NMR (300 MHz, CDCl3) δ 1.12 (t, 3H, J = 6.9 Hz), 3.84 (s, 3H), 3.89 (s, 3H), 4.04−4.21 (m, 2H), 5.65 (s, 1H), 6.82−6.90 (m, 2H), 7.52−7.59 (m, 5H), 7.87− 7.89 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 13.9, 55.8, 55.9, 62.1, 64.0, 106.6, 111.0, 113.1, 122.2, 124.2, 129.4, 131.4, 132.0, 132.3, 138.5, 146.7, 149.0, 167.3, 168.0; FT-IR (film) υmax 1751, 1687, 1541, 1426, 1366, 1217, 1128, 1023, 745 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H20NO5 342.1342, found 342.1355. Ethyl 3-oxo-2-(3,4,5-trimethoxyphenyl)isoindoline-1-carboxylate (5n). Yield of 5n is (346 mg, 94%) as white solid. Rf = 0.2 (30% EtOAc in hexanes, TLC); mp 122−123 °C; 1H NMR (300 MHz, CDCl3) δ 1.13 (t, 3H, J = 7.2 Hz), 3.85 (s, 6H), 3.90 (s, 3H), 4.03−4.20 (m, 2H), 5.59 (s, 1H), 6.82−6.90 (m, 2H), 7.10−7.14 (m, 1H), 7.36 (d, 1H, J = 2.4 Hz), 7.46 (d, 1H, J = 8.4 Hz), 7.52 (d, 1H, J = 2.1 Hz); 13C NMR (75 MHz, CDCl3) δ 14.0, 55.7, 55.9, 56.0, 62.1, 63.8, 106.8, 107.0, 111.1, 113.4, 120.6, 123.2, 130.7, 131.5, 133.6, 146.8, 149.1, 161.0, 167.4, 168.3; FT-IR (film) υmax 1751, 1699, 1593, 1509, 1463, 1236, 1181, 1014, 732 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H22NO6 372.1447, found 372.1455. Ethyl 2-(benzo[d][1,3]dioxol-5-yl)-3-oxoisoindoline-1-carboxylate (5o). Yield of 5o is (300 mg, 93%) as white solid. mp 119−120 °C; Rf = 0.3 (20% EtOAc in hexanes, TLC); 1H NMR (300 MHz, CDCl3) δ 1.14 (t, 3H, J = 7.2 Hz), 4.03−4.21 (m, 2H), 5.60 (s, 1H), 5.95 (s, 2H), 6.78 (d, 1H, J = 8.4 Hz), 6.86−6.89 (m, 1H), 7.29 (d, 1H, J = 1.8 Hz), 7.49−7.58 (m, 3H), 7.88 (d, 1H, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 14.0, 62.2, 64.4, 101.5, 104.9, 108.2, 115.4, 122.3, 124.5, 129.6, 132.0, 132.4, 138.6, 145.5, 148.1, 167.4, 168.0; FT-IR (film) υmax 1749, 1699, 1507, 1489, 1216, 1181, 1034, 737 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C18H16NO5 326.1028, found 326.1018. Ethyl 2-(4-hydroxyphenyl)-3-oxoisoindoline-1-carboxylate (5p). Yield of 5p is (266 mg, 90%) as white solid. Rf = 0.2 (30% EtOAc in hexanes, TLC); mp 120−122 °C; 1H NMR (300 MHz, CDCl3) δ 1.15 (t, 3H, J = 7.2 Hz), 4.05−4.33 (m, 2H), 5.73 (s,1H), 7.26−7.28 (m, 2H), 7.54−7.65 (m, 3H), 7.72−7.75 (m, 2H), 7.93 (d, 2H, J = 7.2 Hz); 13 C NMR (75 MHz, CDCl3) δ 13.9, 62.4, 63.6, 121.7, 122.2, 122.4, 124.6, 129.7, 131.7, 132.8, 136.8, 138.4, 146.0, 167.3, 167.8; FT-IR (film) υmax 3300, 1773, 1689, 1537, 1458, 1353, 1217, 1048, 986, 746 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for [C17H16NO4 298.1079, found 298.1090. Ethyl 3-oxo-2-(pyridin-2-yl)isoindoline-1-carboxylate (5q). Yield of 5q is (274 mg, 93%) as brownish gum. Rf = 0.2 (25% EtOAc in hexanes, TLC); 1H NMR (300 MHz, CDCl3) δ 0.97 (t, 3H, J = 7.2 Hz), 3.88−4.20 (m, 2H), 6.11 (s, 1H), 7.06−7.10 (m, 1H), 7.58−7.68 (m, 3H), 7.78−7.84 (m, 1H), 7.93 (d, 1H, J = 6.9 Hz), 8.27−8.29 (m, 1H), 8.55 (d, 1H, J = 8.4 Hz); 13C NMR (75 MHz, CDCl3) δ 13.6, 22.6, 31.9, 62.5, 89.2, 114.3, 119.7, 122.3, 124.3, 130.7, 133.6, 138.8, 146.7, 150.9, 166.5, 169.8; FT-IR (film) υmax 1754, 1689, 1548, 1418, 1319, 1229, 1138, 1028, 739 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C17H18N2O3 298.1317, found 298.1323. Ethyl 2-(3,4-dimethoxyphenyl)-5-methyl-3-oxoisoindoline-1-carboxylate (9a). Yield of 9a is (316 mg, 90%) as white solid. Rf = 0.2 (25% EtOAc in hexanes, TLC); mp 122−123 °C; 1H NMR (300 MHz, CDCl3) δ 1.16 (t, 3H, J = 7.2 Hz), 2.47 (s, 3H), 3.88 (s, 3H), 3.92 (s, 3H), 4.05−4.23 (m, 2H), 5.64 (s, 1H), 6.88−6.93 (m, 2H), 7.42 (d, 1H, J = 7.8 Hz), 7.50 (d, 1H, J = 7.5 Hz), 7.56 (d, 1H, J = 1.8 Hz), 7.72 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 14.0, 21.4, 56.0, 56.1, 62.1, 64.1, 106.9, 111.3, 113.4, 122.0, 124.6, 131.6, 132.3, 133.4, 136.0, 139.9, 146.9, 149.2, 167.7, 168.4; FT-IR (film) υmax 1757, 1699, 1518, 1437, 1231, 1141, 1030, 760 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H21NO5 356.1498, found 356.1489. F

DOI: 10.1021/acs.joc.8b01049 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry

CDCl3) δ 13.9, 55.8, 55.8, 56.1, 56.2, 61.9, 63.7, 104.2, 105.5, 106.5, 111.1, 112.9, 124.3, 131.6, 132.1, 146.5, 149.0, 150.7, 153.2, 167.5, 168.3; FT-IR (film) υmax 1754, 1697, 1607, 1521, 1377, 1316, 1219, 1028, 749 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C21H24NO7 402.1553, found 402.1547. Ethyl 2-(3,4-dimethoxyphenyl)-4,6-dimethoxy-3-oxoisoindoline1-carboxylate (9j). Yield of 9j is (357 mg, 90%) as white solid. Rf = 0.2 (40% EtOAc in hexanes, TLC); mp 121−122 °C; 1H NMR (300 MHz, DMSO-d6) δ 1.12 (t, 3H, J = 7.2 Hz), 3.76 (s, 6H), 3.86 (s, 3H), 3.88 (s, 3H), 3.99−4.25 (m, 2H), 6.09 (s, 1H), 6.98 (d, 1H, J = 8.7 Hz), 7.07− 7.11 (m, 2H), 7.28 (s, 1H), 7.42 (s, 1H); 13C NMR (75 MHz, DMSOd6) δ 14.2, 55.7, 55.8, 56.1, 56.2, 61.9, 63.0, 104.9, 105.5, 106.6, 112.1, 113.7, 123.8, 131.8, 132.7, 146.3, 148.9, 150.7, 153.3, 166.9, 168.5; FTIR (film) υmax 1751, 1689, 1600, 1521, 1407, 1316, 1211, 1034, 746 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C21H24NO7 402.1553, found 402.1568. tert-Butyl 2-(3,4-dimethoxyphenyl)-3-oxoisoindoline-1-carboxylate (9k). Yield of 9k is (340 mg, 93%) as white solid. Rf = 0.2 (25% EtOAc in hexanes, TLC); mp 120−121 °C; 1H NMR (300 MHz, CDCl3) δ 1.34 (s, 9H), 3.90 (s, 3H), 3.94 (s, 3H), 5.58 (s, 1H), 6.87− 6.97 (m, 2H), 7.55−7.63 (m, 4H), 7.92−7.94 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 27.6, 55.8, 55.9, 64.8, 83.2, 106.3, 110.9, 112.7, 121.9, 124.2, 129.3, 131.7, 132.1, 132.2, 138.8, 146.5, 149.0, 167.0, 167.3; FTIR (film) υmax 1746, 1696, 1512, 1466, 1368, 1241, 1144, 1028, 734 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C21H24NO5 370.1654, found 370.1683. 2-(3,4-Dimethoxyphenyl)-3-(trifluoromethyl)isoindolin-1-one (10). Yield of 10 is (313 mg, 93%) as yellowish solid. Rf = 0.2 (25% EtOAc in hexanes, TLC); mp 124−125 °C; 1H NMR (300 MHz, DMSO-d6) δ 3.64 (s, 3H), 3.72 (s, 3H), 6.83 (d, 2H, J = 8.7 Hz), 6.97 (d, 1H, J = 8.1 Hz), 7.64−7.80 (m, 5H), 8.47 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 55.1, 88.3 (q, J = 28.5 Hz), 111.0, 112.4, 120.9, 122.9, 123.6, 124.5, 126.7, 130.5, 130.9, 132.9, 140.2, 148.0, 148.1, 165.9; FT-IR (film) υmax 1785, 1699, 1522, 1436, 1360, 1231, 1149, 1024, 733 cm−1; HRMS (ESI-TOF) m/z [M − H]+ calcd for C17H13F3NO3 336.0847, found 336.0836. 3-(Hydroxymethyl)-2-(4-methoxyphenyl)isoindolin-1-one (13). Yield of 13 is (82 mg, 96%) as off-white solid. Rf = 0.2 (30% EtOAc in hexanes, TLC); mp 122−123 °C; 1H NMR (300 MHz, CDCl3) δ 3.25 (brs, 1H), 3.59−3.63 (m, 1H), 3.75(s, 3H), 3.91−3.94 (m, 1H), 4.99 (s, 1H), 6.85 (d, 2H, J = 8.4 Hz), 7.31−7.42 (m, 3H), 7.47−7.57 (m, 2H), 7.73 (d, 1H, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 55.4, 61.6, 63.3, 114.4, 122.8, 123.8, 125.9, 128.5, 129.5, 131.9, 132.4, 143.1, 157.7, 168.0; FT-IR (film) υmax 3289, 2925, 1787, 1669, 1502, 1310, 1231, 1119, 1034, 763 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H16NO3 270.1125, found 270.1138. 3-(Hydroxymethyl)isoindolin-1-one (14). Yield of 14 is (52 mg, 50%) as white solid. Rf = 0.3 (80% EtOAc in hexanes, TLC); mp 124− 126 °C; 1H NMR (300 MHz, DMSO-d6) δ 3.49−3.54 (m, 1H), 3.84− 3.97 (m, 1H), 4.70−4.73 (m, 1H), 5.25 (brs, 1H), 7.49 (d, 2H, J = 7.2 Hz), 7.58−7.71 (m, 3H); 13C NMR (75 MHz, DMSO-d6) δ 59.8, 62.6, 128.2, 130.2, 131.7, 132.5, 144.1, 156.9, 166.7; FT-IR (film) υmax 3665, 3291, 1789, 1679, 1513, 1409, 1307, 1129, 1032, 743 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C9H10NO2 164.0706, found 164.0711. 2-(4-Methoxyphenyl)-3-oxoisoindoline-1-carboxylic acid (15). Yield of 15 is (72 mg, 80%) as white solid. Rf = 0.2 (100% EtOAc, TLC); mp 124−126 °C; 1H NMR (300 MHz, DMSO-d6) δ 3.75 (s, 3H), 6.09 (s, 1H), 6.96−7.00 (m, 3H), 7.42 (d, 1H, J = 8.7 Hz), 7.58− 7.81 (m, 4H), 13.44 (brs, 1H); 13C NMR (75 MHz, CDCl3) δ 55.5, 79.3, 114.2, 123.0, 123.4, 125.8, 128.4, 130.2, 131.9, 132.6, 144.2, 157.1, 167.0, 179.1; FT-IR (film) υmax 3350, 1695, 1503, 1426, 1323, 1169, 1034, 960, 736 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H14NO4 284.0923, found 284.0951. Ethyl 5-amino-2-(3,4-dimethoxyphenyl)-3-oxoisoindoline-1-carboxylate (9d). Yield of 9d is (320 mg, 90%) as yellowish gum. Rf = 0.3 (70% EtOAc in hexanes, TLC); 1H NMR (300 MHz, DMSO-d6) δ 1.10 (t, 3H, J = 7.2 Hz), 3.74 (s, 3H), 3.75 (s, 3H), 4.01−4.12 (m, 2H), 5.59 (s, 1H), 5.99 (s, 1H), 6.58 (s, 1H), 6.84−6.91 (m, 2H), 6.96 (d, 1H, J = 8.7 Hz), 7.03−7.16 (m, 1H), 7.26 (d, 1H, J = 8.1 Hz), 7.42 (s, 1H); 13C

Ethyl 2-(3,4-dimethoxyphenyl)-5-methoxy-3-oxoisoindoline-1carboxylate (9b). Yield of 9b is (340 mg, 92%) as white solid. Rf = 0.2 (30% EtOAc in hexanes, TLC); mp 121−122 °C; 1H NMR (300 MHz, CDCl3) δ 1.16 (t, 3H, J = 7.2 Hz), 3.82 (s, 3H), 3.86 (s, 3H), 4.08−4.24 (m, 2H), 5.69 (s, 1H), 6.94 (s, 2H), 7.26−7.61 (m, 3H), 7.90 (d, 1H, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 13.9, 55.9, 60.6, 62.1, 63.9, 99.2, 122.1, 124.1, 128.7, 129.5, 131.3, 131.8, 132.5, 133.9, 135.6, 136.7, 138.4, 153.2, 167.3, 167.9; FT-IR (film) υmax 1752, 1689, 1596, 1503, 1458, 1236, 1171, 1011, 728 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H22NO6 372.1447, found 372.1458. Ethyl 2-(3,4-dimethoxyphenyl)-5-nitro-3-oxoisoindoline-1-carboxylate (9c). Yield of 9c is (360 mg, 94%) as yellowish solid. Rf = 0.2 (25% EtOAc in hexanes, TLC); mp 128−130 °C; 1H NMR (300 MHz, CDCl3) δ 1.17 (t, 3H, J = 7.2 Hz), 3.88 (s, 3H), 3.91 (s, 3H), 4.07−4.28 (m, 2H), 4.78 (s, 1H), 6.86−6.93 (m, 2H), 7.48 (d, 1H, J = 2.1 Hz), 7.81 (d, 1H, J = 8.1 Hz), 8.45−8.49 (m, 1H), 8.70 (d, 1H, J = 1.8 Hz); 13C NMR (75 MHz, CDCl3) δ 13.9, 56.0, 62.8, 64.3, 106.9, 111.2, 113.7, 119.8, 123.6, 127.3, 130.5, 133.9, 144.0, 147.4, 149.3, 149.4, 165.0, 166.8; FT-IR (film) υmax 1757, 1702, 1512, 1351, 1241, 1084, 1022, 732 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H19N2O7 387.1192, found 387.1196. Ethyl 2-(3,4-dimethoxyphenyl)-6-methoxy-3-oxoisoindoline-1carboxylate (9e). Yield of 9e is (340 mg, 92%) as yellowish solid. Rf = 0.2 (30% EtOAc in hexanes, TLC); mp 119−120 °C; 1H NMR (300 MHz, CDCl3) δ 1.13 (t, 3H, J = 7.2 Hz), 3.84 (s, 3H), 3.85 (s, 3H), 3.89 (s, 3H), 4.00−4.23 (m, 2H), 5.59 (s, 1H), 6.82−6.90 (m, 2H), 7.10− 7.14 (m, 1H), 7.36 (d, 1H, J = 2.4 Hz), 7.46 (d, 1H, J = 8.4 Hz), 7.52 (d, 1H, J = 1.8 Hz); 13C NMR (75 MHz, CDCl3) δ 13.9, 55.6, 55.8, 55.9, 62.0, 63.7, 106.7, 107.0, 111.1, 113.3, 120.6, 123.1, 130.7, 131.4, 133.5, 146.8, 149.1, 161.0, 167.4, 168.2; FT-IR (film) υmax 1754, 1692, 1589, 1503, 1469, 1226, 1189, 1032, 727 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H22NO6 372.1447, found 372.1453. Ethyl 6-chloro-2-(3,4-dimethoxyphenyl)-3-oxoisoindoline-1-carboxylate (9f). Yield of 9f is (347 mg, 93%) as white solid. Rf = 0.3 (25% EtOAc in hexanes, TLC); mp 118−120 °C; 1H NMR (300 MHz, CDCl3) δ 1.14 (t, 3H, J = 6.6 Hz), 3.84 (s, 3H), 3.88 (s, 3H), 4.09−4.18 (m, 2H), 5.62 (s, 1H), 6.83 (s, 2H), 7.49 (s, 2H), 7.56 (s, 1H), 7.79 (d, 1H, J = 7.8 Hz); 13C NMR (75 MHz, CDCl3) δ 14.0, 55.9, 62.5, 63.7, 106.7, 111.1, 113.3, 122.7, 125.4, 130.1, 130.6, 131.0, 138.6, 140.0, 147.0, 149.1, 166.3, 167.5; FT-IR (film) υmax 1751, 1699, 1512, 1386, 1242, 1175, 1028, 766 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H19ClNO5 376.0952, found 376.0963. Ethyl 2-(3,4-dimethoxyphenyl)-6-nitro-3-oxoisoindoline-1-carboxylate (9g). Yield of 9g is (357 mg, 93%) as yellowish solid. Rf = 0.2 (30% EtOAc in hexanes, TLC); mp 120−122 °C; 1H NMR (300 MHz, DMSO-d6) δ 1.09 (t, 3H, J = 7.2 Hz), 3.73 (s, 6H), 4.02−4.20 (m, 2H), 6.48 (s, 1H), 6.99 (d, 1H, J = 9.0 Hz), 7.07−7.11 (m, 1H), 7.37 (d, 1H, J = 2.1 Hz), 7.94 (d, 1H, J = 8.4 Hz), 8.42 (d, 1H, J = 2.1 Hz), 8.51 (dd, 1H, J = 2.1 Hz, 8.1 Hz) ; 13C NMR (75 MHz, DMSO-d6) δ 14.0, 55.8, 62.6, 63.8, 107.1, 112.1, 114.6, 118.8, 124.7, 128.0, 130.7, 133.0, 144.8, 147.0, 148.9, 149.2, 164.6, 167.1; FT-IR (film) υmax 1752, 1698, 1511, 1341, 1221, 1107, 1022, 752 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H19N2O7 387.1192, found 387.1186. Ethyl 4-chloro-2-(3,4-dimethoxyphenyl)-3-oxoisoindoline-1-carboxylate (9h). Yield of 9h is (347 mg, 93%) as white solid. Rf = 0.2 (30% EtOAc in hexanes, TLC); mp 115−116 °C; 1H NMR (300 MHz, DMSO-d6) δ 1.15 (t, 3H, J = 7.2 Hz), 3.79 (s, 6H), 4.08−4.26 (m, 2H), 6.33 (s, 1H), 7.03 (d, 1H, J = 9.0 Hz), 7.11−7.15 (m, 1H), 7.44 (d, 1H, J = 2.4 Hz), 7.71−7.74 (m, 2H), 7.86 (d, 1H, J = 8.1 Hz); 13C NMR (75 MHz, DMSO-d6) δ 14.1, 55.8, 62.4, 63.2, 107.0, 112.0, 114.3, 122.9, 125.6, 130.3, 130.6, 131.0, 137.8, 141.0, 146.8, 148.9, 165.5, 167.7; FTIR (film) υmax 1753, 1689, 1516, 1366, 1239, 1145, 1021, 746 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H19ClNO5 376.0952, found 376.0969. Ethyl 2-(3,4-dimethoxyphenyl)-5,6-dimethoxy-3-oxoisoindoline1-carboxylate (9i). Yield of 9i is (366 mg, 92%) as white solid. Rf = 0.2 (40% EtOAc in hexanes, TLC); mp 123−124 °C; 1H NMR (300 MHz, CDCl3) δ 1.10 (t, 3H, J = 7.2 Hz), 3.84 (s, 3H), 3.89 (s, 3H), 3.92 (s, 3H), 3.93 (s, 3H), 4.00−4.24 (m, 2H), 5.55 (s, 1H), 6.81−6.87 (m, 2H), 7.02 (s, 1H), 7.33 (s, 1H), 7.52 (s, 1H); 13C NMR (75 MHz, G

DOI: 10.1021/acs.joc.8b01049 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry NMR (75 MHz, DMSO-d6) δ 19.1, 60.8, 60.9, 66.8, 68.0, 111.7, 112.1, 116.6, 117.0, 118.8, 124.1, 128.0, 131.1, 136.8, 137.6, 151.4, 153.8, 153.9, 155.4, 172.4, 174.0; FT-IR (film) υmax 3432, 1751, 1699, 1518, 1407, 1311, 1232, 1022, 737 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H21N2O5 357.1450, found 357.1439. Methyl 2-(1-(3,4-dimethoxyphenylamino)-2-ethoxy-2-oxoethyl)4,5-difluorobenzoate (17). Yield of 17 is (93%) as brownish gum. Rf = 0.2 (30% EtOAc in hexanes); 1H NMR (300 MHz, CDCl3) δ 1.18 (t, 3H, J = 7.2 Hz), 3.73 (s, 3H), 3.76 (s, 3H), 3.89 (s, 3H), 4.01−4.26 (m, 2H), 4.84 (brs, 1H), 5.30 (s, 1H), 5.96−6.00 (m, 1H), 6.25 (d, 1H, J = 2.1 Hz), 6.63 (d, 1H, J = 8.4 Hz), 7.56 (d, 1H, J = 9.6 Hz), 7.72 (d, 1H, J = 6.3 Hz); 13C NMR (75 MHz, CDCl3) δ 13.8, 52.6, 54.2, 55.5, 56.3, 62.4, 99.5, 103.8, 112.8, 116.6, 118.7 (d, J = 25.5 Hz), 131.1 (d, J = 14.2 Hz), 132.8 (d, J = 7.5 Hz), 133.8, 139.7, 142.3, 149.8, 157.5, 160.8, 164.9, 169.9; FT-IR (film) υmax 3377, 1724, 1619, 1518, 1437, 1231, 1030, 760 cm−1.

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Jiang, D.; Dai, L.-Y.; Li, C.-J. Development of a copper(II)-catalyzed three-component tandem synthesis of isoindolinone derivatives. Can. J. Chem. 2012, 90, 92−99. (d) Dhanasekaran, S.; Suneja, A.; Bisai, V.; Singh, V. K. Approach to Isoindolinones, Isoquinolinones, and THIQs via Lewis Acid-Catalyzed Domino Strecker-Lactamization/Alkylations. Org. Lett. 2016, 18, 634−637. (3) (a) Chinchilla, R.; Nájera, C. Acylvinyl and Vinylogous Synthons. Chem. Rev. 2000, 100, 1891−1928. (b) Riant, O.; Hannedouche, J. Asymmetric catalysis for the construction of quaternary carbon centres: nucleophilic addition on ketones and ketimines. Org. Biomol. Chem. 2007, 5, 873−888. (c) Cativiela, C.; Díaz-de-Villegas, M. D. Recent progress on the stereoselective synthesis of acyclic quaternary α-amino acids. Tetrahedron: Asymmetry 2007, 18, 569−623. (d) Ackermann, L.; Vicente, R.; Kapdi, A. R. Transition-Metal-Catalyzed Direct Arylation of (Hetero)Arenes by CH Bond Cleavage. Angew. Chem., Int. Ed. 2009, 48, 9792−9826. (e) Chiba, S.; Chen, H. sp3 C−H oxidation by remote H-radical shift with oxygen- and nitrogen-radicals: a recent update. Org. Biomol. Chem. 2014, 12, 4051−4060. (4) Wieland, L. C.; Vieira, E. M.; Snapper, M. L.; Hoveyda, A. H. AgCatalyzed Diastereo- and Enantioselective Vinylogous Mannich Reactions of α-Ketoimine Esters. Development of a Method and Investigation of its Mechanism. J. Am. Chem. Soc. 2009, 131, 570−576. (5) (a) Zhao, P.; Wang, F.; Han, K.; Li, X. Rhodium(III)-Catalyzed Cyclization−Olefination of N-Acetoxyl Ketoimine-Alkynes. Org. Lett. 2012, 14, 3400−3403. (b) Simal, C.; Lebl, T.; Slawin, A. M. Z.; Smith, A. D. Dihydropyridones: Catalytic Asymmetric Synthesis, N-to CSulfonyl Transfer, and Derivatizations. Angew. Chem., Int. Ed. 2012, 51, 3653−3657. (c) Stark, D. G.; O’Riordan, T. J. C.; Smith, A. D. Synthesis of Di-, Tri-, and Tetrasubstituted Pyridines from (Phenylthio)carboxylic Acids and 2-[Aryl(tosylimino)methyl]acrylates. Org. Lett. 2014, 16, 6496−6499. (d) Yeh, P.-P.; Daniels, D. S. B.; Fallan, C.; Gould, E.; Simal, C.; Taylor, J. E.; Slawin, A. M. Z.; Smith, A. D. Exploring the scope of the isothiourea-mediated synthesis of dihydropyridinones. Org. Biomol. Chem. 2015, 13, 2177−2191. (e) Xu, J.; Yuan, S.; Peng, J.; Miao, M.; Chen, Z.; Ren, H. Enantioselective [2 + 2] annulation of simple aldehydes with isatinderived ketimines via oxidative N-heterocyclic carbene catalysis. Chem. Commun. 2017, 53, 3430−3433. (f) Qiang, L.; Xiang-Yu, C.; Sun, L.; Ehsan, J.; Gerhard, R.; Dieter, E. N-Heterocyclic carbene-catalyzed [4 + 2] annulation of β-methyl enals and cyclic trifluoromethyl ketimines for the asymmetric synthesis of dihydroquinazolinone derivatives. Chem. Commun. 2017, 53, 11342−11344. (6) (a) Pandit, P.; Chatterjee, N.; Maiti, D. K. First synthesis of fusedΔ1-pyrrolines via intramolecular 1,3-dipolar cycloaddition of ketoimine: A complete diastereoselective approach. Chem. Commun. 2011, 47, 1285−1287. (b) Li, E.; Jin, H.; Jia, P.; Dong, X.; Huang, Y. Bifunctional-Phosphine-Catalyzed Sequential Annulations of Allenoates and Ketimines: Construction of Functionalized Poly-heterocycle Rings. Angew. Chem., Int. Ed. 2016, 55, 11591. (c) He, Q.; Du, W.; Chen, Y.-C. Asymmetric [3+ 2] Annulations to Construct 1, 2Bispirooxindoles Incorporating a Dihydropyrrolidine Motif. Adv. Synth. Catal. 2017, 359, 3782−3791. (d) Nakamura, S.; Furukawa, T.; Hatanaka, T.; Funahashi, Y. Enantioselective aza-Friedel−Crafts reaction of cyclic ketimines with indoles using chiral imidazoline− phosphoric acid catalysts. Chem. Commun. 2018, 54, 3811−3814. (7) Eisenbeis, S. A.; Chen, R.; Kang, M.; Barrila, M.; Buzon, R. Utilization of ReactIR in Fit for Purpose Process Enablement. Org. Process Res. Dev. 2015, 19, 244−248. (8) (a) Trivedi, S.; Dekermendjian, K.; Julien, R.; Huang, J.; Lund, P.E.; Krupp, J.; Kronqvist, R.; Larsson, O.; Bostwick, R. Cellular HTS Assays for Pharmacological Characterization of NaV1.7 Modulators. Assay Drug Dev. Technol. 2008, 6, 167−179. (b) Macsari, I.; Besidski, Y.; Csjernyik, G.; Nilsson, L. I.; Sandberg, L.; Yngve, U.; Åhlin, K.; Bueters, T.; Eriksson, A. B.; Lund, P.-E.; Venyike, E.; Oerther, S.; Blakeman, K. H.; Luo, L.; Arvidsson, P. 3-Oxoisoindoline-1-carboxamides: Potent, State-Dependent Blockers of Voltage-Gated Sodium Channel NaV1.7 with Efficacy in Rat Pain Models. J. Med. Chem. 2012, 55, 6866−6880. (9) (a) Goa, K. L.; Heel, R. C. Zopiclone. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01049. ESI-MS kinetics and photophysical data, and NMR spectra of new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Dilip K. Maiti: 0000-0001-8743-2620 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support of D. S. Kothari, UGC (AK) (No. F.4-2/2006 (BSR)/CH/16-17/0058), CSIR (JRF to SA), SERB (SP) (PDF/2016/001479) and CSIR (Project No. 02(0250)/15/ EMR-II) are gratefully acknowledged.

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REFERENCES

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DOI: 10.1021/acs.joc.8b01049 J. Org. Chem. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.joc.8b01049 J. Org. Chem. XXXX, XXX, XXX−XXX