Stereoselective Synthesis of Pyrroloisoindolone and

May 1, 2018 - (4) Owing to their diverse biological activity, development of newer ... The reaction in the presence of molecular sieves (Table 1, entr...
6 downloads 0 Views 1MB Size
Download PDF
Note pubs.acs.org/joc

Cite This: J. Org. Chem. 2018, 83, 6178−6185

Stereoselective Synthesis of Pyrroloisoindolone and Pyridoisoindolone via aza-Prins Cyclization of Endocyclic N‑Acyliminium Ions Malay Das and Anil K. Saikia* Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, India S Supporting Information *

ABSTRACT: A simple methodology has been developed for the synthesis of substituted pyrroloisoindolone and pyridoisoindolone via aza-Prins cyclization of endocyclic N-acyliminium ions, which are derived from the triflic acid treatment of regioselectively reduced N-homopropargyl imides in excellent yields. The reaction is highly diastereoselective, and only one diastereoisomer is formed during the reaction. The methodology can be utilized for the synthesis of pyrimidoisoindole.

P

derivatives having a carbonyl moiety in the side chain with very high diasteroselectivity. To start with, 3-hydroxy-2-(4-phenylbut-3-yn-1-yl)isoindolin-1-one 1a (Table 1, entry 1) was treated with borontrifluoride etherate (BF3·OEt2) in dry dichloromethane at 0 °C for 12 h, but the reaction resulted in a mixture of complex products. Other Lewis acids, such as indium chloride (InCl3) (Table 1, entry 2), also produced complex products, while ferric chloride (FeCl3), indium(III) trifluoromethanesulfonate (In-

yrroloisoindolone and pyridoisoindolone skeletons are found in many biologically active molecules and natural products. For example, N-[(9bS)-5-oxo-2,3,5,9b-tetrahydro-1Hpyrrolo[2,1-a]-isoindol-9-yl]-N′-[5-({[(2S)-5-chloro-2,3-dihydro-1H-inden-2-yl]amino}- methyl)-1H-pyrazol-3-yl]urea is a potent Cdk4 inhibitor,1 whereas tetrahydropyrido[1,2-a]isoindolone derivatives (valmerin vitamins) are potent cyclindependent kinase/glycogen synthase kinase-3 inhibitors and also exhibit antitumor activities.2 On the other hand, pyrroloisoindolone derivatives are urotensin-II receptor antagonists.3 Apart from their existence in biologically active molecules, these skeletons are present in many natural products.4 Owing to their diverse biological activity, development of newer methodology for construction of such structures is of particular interest, and numerous methodologies have been developed in recently. N-Acyliminium ions are versatile reaction intermediates in the construction of N-heterocyclic scaffolds. Due to the presence of the carbonyl group, the Nacyliminium ions are highly reactive electrophiles,5 and several groups have utilized this intermediate for the construction of a range of structurally diverse compounds via intra- and intermolecular nucleophilic substitution,6 cationic polycyclization,7 and ring expansions of β-lactams, leading to γ-lactams.8 There are different methods for the synthesis of isoindolones starting from 2-formylbenzoic acid and esters or from βhydroxy lactones via acyl iminium ions;9 carboxybenzaldehyde;10 N-acyliminium ion cyclizations of trimethylsilylmethylallenes;11 cyclization of 2-bromo-3-nitrobenzoic acid,4 nitrophthalimide,2 and vinyl sulfides;12 and Aza-Nazarov cyclization cascades.13 Recently we have developed a methodology for the synthesis of amido- and tosylated aza-bicyclic compounds, including isoindolone derivatives using the aza-Prins cyclization reaction of the N-acyliminium ion intermediate.14 Although it gives good yields, it suffers from low diastereoselectivity in some cases. Herein, we would like to present a methodology for the synthesis of pyrroloisoindolone and pyridoisoindolone © 2018 American Chemical Society

Table 1. Optimization of the Reaction

entry

reagent (equiv)

solvent

time (h)

yielda(%)

1 2 3 4 5 6 7 8 9 10 11 12

BF3·OEt2 (1.1) InCl3(1.2) FeCl3(1.2) In(OTf)3 (1.1) TMSOTf (1.1) CF3CO2H (1.1) TfOH (1.2) TfOH (0.1) TfOH (1.2)/MS TfOH (1.1) TfOH (1.1) pTsOH (1.1)

CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH3CN toluene CH2Cl2

12 12 12 12 12 12 12 24 12 12 12 24

db db 47 40 60 45 70 25 65 db db 0b

a

Yields are isolated yield. bStarting material recovered. d = Complex mixture. MS = Molecular sieves Received: February 15, 2018 Published: May 1, 2018 6178

DOI: 10.1021/acs.joc.8b00440 J. Org. Chem. 2018, 83, 6178−6185

Note

The Journal of Organic Chemistry Table 2. Synthesis of Pyrrolo- and Pyridoisoindolone via aza-Prins Cyclization Reaction

a

Yield refers to isolated yield. The compounds were characterized by IR, NMR, and mass spectrometry. bNo reactions. Starting material was recovered in 95% yield.

(OTf) 3 ), and trimethylsilyl trifluoromethanesulfonate (TMSOTf) (Table 1, entries 3−5) gave 3-hydroxy-2-(4phenylbut-3-yn-1-yl)isoindolin-1-one 2a as a single diastereomer in 47, 40, and 60% yields, respectively. The Brønsted acid, trifluoroacetic acid (Table 1, entry 6), was also found to be effective for the reaction but with a lower yield. Trifluoromethanesulfonic acid (triflic acid) (Table 1, entry 7) in

dichloromethane under similar conditions gave a 70% yield. The same reaction under a catalytic amount of triflic acid only gave a 25% yield even after exposure to a long duration of time (Table 1, entry 8). The reaction in the presence of molecular sieves (Table 1, entry 9) gave a 65% yield. Other solvents, such as acetonitrile and toluene (Table 1, entries 10−11), are found to be ineffective and produced a mixture of complex products. 6179

DOI: 10.1021/acs.joc.8b00440 J. Org. Chem. 2018, 83, 6178−6185

Note

The Journal of Organic Chemistry The other Bronsted acid, p-toluenesulfonic acid (p-TsOH) (Table 1, entry 12), did not give the desired product, but the starting material was recovered after a prolonged reaction for 24 h. With these optimum reaction conditions in hand, the scope of the reaction was investigated with a variety of substrates, 1a− 1n (Table 2), which were prepared from a literature procedure.14 It was observed from Table 2 that the success of the reaction depends on the substituents in the alkyne side chain. Substrates having electron donating groups on the aromatic ring (Table 2, entries 5−7) gave pyrroloisoindolone in good yields compared to simple phenyl (Table 2, entry 1) and moderate electron withdrawing groups in the aromatic ring (Table 2, entries 2−4). On the contrary, the terminal alkyne (Table 2, entry 8) and the alkyl-substituted alkyne (Table 2, entry 9) failed to give the desired product; instead, the starting materials were recovered in a 95% yield. This might be due to the instability of the carbocation intermediate B formed during the reaction (Scheme 2). Similarly, pyridoisoindolones, 2j−2n and 2p, can be synthesized from substrates 1j−1n and 1p in good yields. These substrates also follow a similar trend in terms of the reactivity of like substrates, 1a−1h. Highly electron withdrawing nitro groups on the aromatic ring of the substrate 1o reduce the nucleophilicity of the alkyne group, which is responsible for the recovery of the starting material. Ortho- and meta-substituted aromatic moieties in the alkyne side chain did not affect the rate of the reaction (Table 2, entries 6, 13). The heteroaryl substituent in the alkyne side (Table 2, entry 16) also worked well with producing compound 2p in a 60% yield. The structure of all of the compounds was determined with the help of 1H and 13C NMR and mass spectrometry. The relative stereochemistry of the compounds was confirmed by X-ray crystallographic analysis of compound 2b (see SI).15 The scope of the reaction was further exemplified with the synthesis of pyrimidoisoindole 2q. The N-alkylnitrile substituted substrate 1q under similar reaction conditions produced pyrimidoisoindole 2q in a 65% yield (Scheme 1). Importantly, pyrimido[2,1- a]isoindoles exhibit many biological properties, namely anxiolytic,16 vasorelaxant,17 antiplasmodial,18 and antifungal19 activities.

Scheme 2. Plausible Reaction Mechanism

(Scheme 2). Another possibility is the formation of most stable compound 2 by equilibration of the initially formed compounds 2 and 3 via enolization under acidic conditions. To confirm the carbocation formation, the intermediate B was trapped with methanol under anhydrous conditions to give (E)-1-(methoxy(phenyl)methylene)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindol-5(9bH)-one 4 in a 62% yield, the E-geometry, which was determined by a NOE experiment (see SI) (Scheme 3). In order to prove that the product is the result of a Scheme 3. Trapping of Carbocation B with Methanol

thermodynamically controlled reaction, compounds 2b and 2c were treated with KOH in dry methanol (eq 1), and it was observed that the ratio of the diastereomers 2b:3b and 2c:3c were 77:23 and 71:29, respectively (Scheme 4). Importantly, when the two diastereomers 2b and 3b were treated with triflic

Scheme 1. Synthesis of Pyrimidoisoindole

Scheme 4. Reaction of 2b−2c with KOH The mechanism of the reaction can be explained as follows. Trifluoromethanesulfonic acid generates N-acyliminium ion A from carbinol 1, which after the aza-Prins cyclization reaction forms carbocation B. The carbocation B is trapped by water during the work up20 of the reaction to generate enols C and C′ (Scheme 2). The enols C and C′, after tautomerization, give thermodynamically more stable tricyclic azo-compounds 2, in which the benzoyl group is exo to the pyrroloisoindolone and pyridoisoindolone ring system. On the other hand, the benzoyl group is endo to the pyrroloisoindolone and pyridoisoindolone ring in compound 3, making it unstable due to the repulsion between the benzoyl group and the isoindolinone moiety 6180

DOI: 10.1021/acs.joc.8b00440 J. Org. Chem. 2018, 83, 6178−6185

Note

The Journal of Organic Chemistry

Yield 324 mg, 55%. 1H NMR (600 MHz, CDCl3, δ): 2.74 (t, J = 6.6 Hz, 2 H), 3.48 (brs, 1 H), 3.60−3.65 (m, 1 H), 3.69−3.73 (m, 1 H), 5.96 (s, 1 H), 6.95 (t, J = 8.4 Hz, 2 H), 7.28−7.31 (m, 2 H), 7.48 (t, J = 7.8 Hz, 1 H), 7.59 (t, J = 7.8 Hz, 1 H), 7.62 (d, J = 7.2 Hz, 1 H), 7.66 (d, J = 7.2 Hz, 1 H). 13CNMR (150 MHz, CDCl3, δ): 19.6, 38.6, 81.4, 82.6, 86.9, 115.7 (d, J = 21.9 Hz), 119.4 (d, J = 3.4 Hz), 123.5 (d, J = 13.8 Hz), 130.1, 131.5, 132.6, 133.5, 133.6, 144.1, 162.5 (d, J = 247.5 Hz), 167.8; 19F NMR (376 MHz, CDCl3/C6F6, δ): 50.25. IR (KBr, neat): 3269, 2926, 1674, 1124, 1064, 747 cm−1. HRMS (ESI): (M + H)+ calcd for C18H15FNO2, 296.1081; found, 296.1078. 3-Hydroxy-2-(4-(p-tolyl)but-3-yn-1-yl)isoindolin-1-one (1e). Brown solid. Rf (hexane/EtOAc 1:1) 0.6. mp 180−182 °C. Yield 340 mg, 67%. 1H NMR (400 MHz, CDCl3, δ): 2.31 (s, 3 H), 2.71 (t, J = 6.0 Hz, 2 H), 3.52−3.66 (m, 2 H), 4.09 (d, J = 11.2 Hz, 1 H), 5.96 (d, J = 11.2 Hz, 1 H), 7.05 (d, J = 7.6 Hz, 2 H), 7.20 (d, J = 7.6 Hz, 2 H), 7.44 (t, J = 7.2 Hz, 1 H), 7.56 (t, J = 7.6 Hz, 1 H), 7.60 (d, J = 7.6 Hz, 2 H). 13CNMR (150 MHz, CDCl3, δ): 19.8, 21.7, 39.0, 82.5, 82.6, 86.7, 120.3, 123.6, 129.2, 129.3, 130.1, 131.6, 131.7, 132.6, 138.3, 144.1, 167.6. IR (KBr, neat): 3258, 2919, 1676, 1179, 1064, 745 cm−1. HRMS (ESI): (M + H)+ calcd for C19H18NO2, 292.1332; found, 292.1322. 3-Hydroxy-2-(4-(o-tolyl)but-3-yn-1-yl)isoindolin-1-one (1f). Colorless solid. Rf (hexane/EtOAc 1:1) 0.57. mp 103−105 °C. Yield 384 mg, 66%. 1H NMR (600 MHz, CDCl3, δ): 2.30 (s, 3 H), 2.80 (t, J = 6.6 Hz, 2 H), 3.57−3.62 (m, 1 H), 3.67−3.72 (m, 2 H), 5.98 (d, J = 11.4 Hz, 1 H), 7.07 (t, J = 7.2 Hz, 1 H), 7.12−7.17 (m, 2 H), 7.28 (d, J = 7.2 Hz, 1 H), 7.46 (t, J = 7.2 Hz, 1 H), 7.57 (t, J = 7.2 Hz, 1 H), 7.61 (d, J = 7.2 Hz, 1 H), 7.64 (d, J = 7.2 Hz, 1 H). 13CNMR (150 MHz, CDCl3, δ): 19.7, 20.8, 38.7, 81.3, 82.5, 91.0, 123.2, 123.5, 123.6, 125.7, 128.1, 129.6, 130.0, 131.5, 132.1, 132.6, 140.2, 144.2, 167.8. IR (KBr, neat): 3376, 2923, 1711, 1129, 1064, 744 cm−1. HRMS (ESI): (M + H)+ calcd for C19H18NO2, 292.1332; found, 292.1337. 3-Hydroxy-2-(4-(4-methoxyphenyl)but-3-yn-1-yl)isoindolin-1one (1g). Brown solid. Rf (hexane/EtOAc 1:1) 0.5. mp 150−152 °C. Yield 417 mg, 68%. 1H NMR (400 MHz, CDCl3, δ): 2.75 (t, J = 6.8 Hz, 2 H), 3.45 (d, J = 11.2 Hz, 1 H), 3.60−3.68 (m, 1 H), 3.70−3.77 (m, 1 H), 3.78 (s, 3 H), 5.98 (d, J = 11.2 Hz, 1 H), 6.78 (d, J = 6.8 Hz, 2 H), 7.26 (d, J = 6.8 Hz, 2 H), 7.47 (dt, J = 7.2 and 1.2 Hz, 1 H), 7.55−7.62 (m, 2 H), 7.69 (d, J = 7.2 Hz, 1 H). 13CNMR (150 MHz, CDCl3, δ): 19.8, 38.9, 55.5, 82.2, 82.6, 85.8, 114.1, 115.5, 123.5, 123.6, 130.1, 131.6, 132.6, 133.1, 144.1, 159.5, 167.7. IR (KBr, neat): 3365, 2931, 1679, 1176, 1030, 746 cm−1. HRMS (ESI): (M + H)+ calcd for C19H18NO3, 308.1281; found, 308.1263. 2-(But-3-yn-1-yl)-3-hydroxyisoindolin-1-one (1h). Colorless solid. Rf (hexane/EtOAc 1:1) 0.5. mp 91−93 °C. Yield 201 mg, 50%. 1H NMR (600 MHz, CDCl3, δ): 1.97 (t, J = 3.0 Hz, 1 H), 2.50−2.52 (m, 2 H), 3.49−3.51(m, 1 H), 3.53−3.56 (m, 1 H), 3.93 (brs, 1 H), 5.93 (d, J = 11.4 Hz, 1 H), 7.45 (t, J = 7.2 Hz, 1 H), 7.56−7.62 (m, 3 H). 13 CNMR (150 MHz, CDCl3, δ): 18.6, 38.2, 70.4, 81.8, 82.4, 123.4, 123.6, 129.9, 131.3, 132.6, 144.2, 167.8. IR (KBr, neat): 3295, 2923, 1681, 1130, 1058, 747 cm−1. HRMS (ESI): (M + H)+ calcd for C12H12NO2, 202.0863; found, 202.0865. 2-(Hex-3-yn-1-yl)-3-hydroxyisoindolin-1-one (1i). Colorless solid. Rf (hexane/EtOAc 1:1) 0.5. mp 95−97 °C. Yield 243 mg, 53%. 1H NMR (400 MHz, CDCl3, δ): 1.04 (t, J = 7.2 Hz, 3 H), 2.07−2.13 (m, 2 H), 2.44−2.49 (m, 2 H), 3.44−3.50 (m, 1 H), 3.51−3.57 (m, 1 H), 3.83 (d, J = 11.2 Hz, 1 H), 5.92 (d, J = 11.2 Hz, 1 H), 7.45 (t, J = 7.6 Hz, 1 H), 7.54−7.62 (m, 3 H). 13CNMR (150 MHz, CDCl3, δ): 12.5, 14.2, 19.0, 39.0, 77.0, 82.5, 83.9, 123.5, 123.6, 130.0, 131.6, 132.5, 144.2, 167.7. IR (KBr, neat): 3330, 2937, 1681, 1127, 1063, 746 cm−1. HRMS (ESI): (M + H)+ calcd for C14H16NO2, 230.1176; found, 230.1176. 3-Hydroxy-2-(5-phenylpent-4-yn-1-yl)isoindolin-1-one (1j). Brown solid. Rf (hexane/EtOAc 1:1) 0.6. mp 93−95 °C. Yield 349 mg, 60%. 1H NMR (400 MHz, CDCl3, δ): 1.82−1.95 (m, 2 H), 2.34− 2.47 (m, 2 H), 3.40−3.54 (m, 2 H), 4.31 (brs, 1 H), 5.78 (d, J = 11.2 Hz, 1 H), 7.21−7.27 (m, 5 H), 7.38 (t, J = 7.6 Hz, 1 H), 7.47−7.56 (m, 3 H). 13CNMR (150 MHz, CDCl3, δ): 17.5, 27.4, 38.9, 81.5, 82.2, 89.2, 123.3, 123.5, 123.8, 127.8, 128.3, 129.9, 131.6, 131.7, 132.4, 144.2, 168.0. IR (KBr, neat): 3331, 2926, 1678, 1127, 1060, 750 cm−1.

acid under the optimized reaction conditions, there was no change in the ratio of diastereomers (eq 2). This indicated that the final product was formed due to the stability of diastereomer 2 but not via enolization of initially formed products 2 and 3 in acidic medium. In conclusion, we have developed a methodology for the synthesis of substituted pyrroloisoindolone and pyridoisoindolone via aza-Prins cyclization of endocyclic N-acyliminium ions. The reaction is atom economic, and good yields are achieved with high diastereoselectivity. The reaction can also be extended for the synthesis of pyrimidoisoindole in good yield.

■

EXPERIMENTAL SECTION

General Information. All of the reagents were of reagent grade (AR grade) and were used as purchased without further purification. Silica gel (60−120 mesh size) was used for column chromatography. Reactions were monitored by TLC on silica gel GF254 (0.25 mm). Melting points were recorded in an open capillary tube and are uncorrected. Fourier transform-infrared (FT-IR) spectra were recorded either as neat liquid or KBr pellets. NMR spectra were recorded in CDCl3 with tetramethylsilane as the internal standard for 1 H (600, 400 MHz) or 13C (150, 100 MHz). Chemical shifts (δ) are reported in ppm and spin−spin coupling constants (J) are given in Hz. HRMS spectra were recorded using Q-TOF mass spectrometer. General Procedure for Synthesis of Starting Materials. To a stirred solution of homopropargyl imides (2 mmol) in MeOH (10 mL), was added NaBH4 (4 equiv) at 0 °C, and the mixture was stirred for an hour. After completion of the reaction, saturated sodium bicarbonate solution (10 mL) was added, and the organic layer was extracted with dichloromethane (2 × 20 mL). The organic phase was washed with brine and dried over anhydrous Na2SO4. Evaporation of the solvent gave the crude product, which was purified by column chromatography over silica gel using ethyl acetate and hexane as the eluent to give the carbinol amides 1a−1q. 3-Hydroxy-2-(4-phenylbut-3-yn-1-yl)isoindolin-1-one (1a). Colorless solid. Rf (hexane/EtOAc 1:1) 0.57. mp 105−107 °C. Yield 343 mg, 62%. 1H NMR (600 MHz, CDCl3, δ): 2.72−2.74 (m, 2 H), 3.55− 3.62 (m, 1 H), 3.63−3.67 (m, 1 H), 3.95 (brs, 1 H), 5.96 (s, 1 H), 7.24−7.26 (m, 3 H), 7.30−7.32 (m, 2 H), 7.42−7.47 (m, 1 H), 7.56 (t, J = 7.2 Hz, 1 H), 7.60 (d, J = 7.2 Hz, 2 H). 13CNMR (150 MHz, CDCl3, δ): 19.6, 38.6, 82.4, 82.5, 87.2, 123.4, 123.5, 123.6, 128.1, 128.5, 130.0, 131.4, 131.7, 132.6, 144.2, 167.9. IR (KBr, neat): 3336, 2853, 1679, 1105, 1061, 748 cm−1. HRMS (ESI): (M + H)+ calcd for C18H16NO2, 278.1176; found, 278.1175. 2-(4-(4-Chlorophenyl)but-3-yn-1-yl)-3-hydroxyisoindolin-1-one (1b). Brown solid. Rf (hexane/EtOAc 1:1) 0.6. mp 148−150 °C. Yield 404 mg, 65%. 1H NMR (600 MHz, CDCl3, δ): 2.75 (t, J = 6.0 Hz, 2 H), 3.55 (d, J = 11.4 Hz, 1 H), 3.60−3.64 (m, 1 H), 3.68−3.73 (m, 1 H), 5.94 (d, J = 11.4 Hz, 1 H), 7.21−7.25 (m, 4 H), 7.47 (t, J = 7.2 Hz, 1 H), 7.58 (t, J = 7.2 Hz, 1 H), 7.61 (d, J = 7.2 Hz, 1 H), 7.65 (d, J = 7.2 Hz, 1 H). 13CNMR (150 MHz, CDCl3, δ): 19.6, 38.4, 81.4, 82.5, 88.2, 121.9, 123.4, 123.6, 128.8, 130.0, 131.3, 132.6, 133.0, 134.1, 144.2, 167.9. IR (KBr, neat): 3268, 2914, 1672, 1120, 1065, 745 cm−1. HRMS (ESI): (M + H)+ calcd for C18H15ClNO2, 312.0786; found, 312.0783. 2-(4-(4-Bromophenyl)but-3-yn-1-yl)-3-hydroxyisoindolin-1-one (1c). Colorless solid. Rf (hexane/EtOAc 1:1) 0.6. mp 158−160 °C. Yield 426 mg, 60%. 1H NMR (600 MHz, CDCl3, δ): 2.64 (t, J = 6.0 Hz, 2 H), 3.47−3.52 (m, 1 H), 3.55−3.60 (m, 1 H), 3.83 (d, J = 11.4 Hz, 1 H), 5.85 (d, J = 11.4 Hz, 1 H), 7.09 (d, J = 8.4 Hz, 2 H), 7.30 (d, J = 8.4 Hz, 2 H), 7.37 (t, J = 7.2 Hz, 1 H), 7.49 (t, J = 7.2 Hz, 1 H), 7.53 (d, J = 7.2 Hz, 2 H). 13CNMR (150 MHz, CDCl3, δ): 19.7, 38.4, 81.4, 82.5, 88.5, 122.3, 122.4, 123.5, 123.6, 130.1, 131.4, 131.7, 132.7, 133.2, 144.2, 167.8. IR (KBr, neat): 3399, 2920, 1673, 1120, 1065, 745 cm−1. HRMS (ESI): (M + H)+ calcd for C18H15BrNO2, 356.0281; found, 356.0284 (79Br). 2-(4-(4-Fluorophenyl)but-3-yn-1-yl)-3-hydroxyisoindolin-1-one (1d). Colorless solid. Rf (hexane/EtOAc 1:1) 0.6. mp 133−135 °C. 6181

DOI: 10.1021/acs.joc.8b00440 J. Org. Chem. 2018, 83, 6178−6185

Note

The Journal of Organic Chemistry HRMS (ESI): (M + H)+ calcd for C19H18NO2, 292.1332; found, 292.1337. 2-(5-(4-Bromophenyl)pent-4-yn-1-yl)-3-hydroxyisoindolin-1-one (1k). Pale yellow solid. Rf (hexane/EtOAc 1:1) 0.64. mp 106−108 °C. Yield 458 mg, 62%. 1H NMR (600 MHz, CDCl3, δ): 1.87−1.96 (m, 2 H), 2.37−2.47 (m, 2 H), 3.45−3.50 (m, 1 H), 3.54−3.59 (m, 1 H), 3.71 (d, J = 11.4 Hz, 1 H), 5.79 (d, J = 11.4 Hz, 1 H), 7.09 (d, J = 8.4 Hz, 2 H), 7.34 (d, J = 8.4 Hz, 2 H), 7.41 (t, J = 7.8 Hz, 1 H), 7.52 (t, J = 7.8 Hz, 1 H), 7.57 (t, J = 7.8 Hz, 2 H). 13CNMR (150 MHz, CDCl3, δ): 17.5, 27.3, 39.0, 80.5, 82.3, 90.6, 122.0, 122.7, 123.4, 123.5, 130.0, 131.6, 131.7, 132.5, 133.2, 144.1, 167.9. IR (KBr, neat): 3329, 2928, 1677, 1126, 1066, 745 cm−1. HRMS (ESI): (M + H)+ calcd for C19H17BrNO2, 370.0437; found, 370.0439 (79Br). 3-Hydroxy-2-(5-(p-tolyl)pent-4-yn-1-yl)isoindolin-1-one (1l). Pale yellow solid. Rf (hexane/EtOAc 1:1) 0.62. mp 109−111 °C. Yield 396 mg, 65%. 1H NMR (400 MHz, CDCl3, δ): 1.84−1.93 (m, 2 H), 2.30 (s, 3 H), 2.36−2.44 (m, 2 H), 3.39−3.53 (m, 2 H), 4.30 (brs, 1 H), 5.77 (d, J = 10.8 Hz, 1 H), 7.02 (d, J = 8.0 Hz, 2 H), 7.14 (d, J = 8.0 Hz, 2 H), 7.38 (t, J = 7.2 Hz, 1 H), 7.48−7.57 (m, 3 H). 13CNMR (150 MHz, CDCl3, δ): 17.4, 21.6, 27.4, 38.9, 81.5, 82.2, 88.4, 120.7, 123.3, 123.5, 129.1, 129.8, 131.6, 132.4 (2C), 137.8, 144.2, 168.0. IR (KBr, neat): 3332, 2924, 1678, 1126, 1058, 746 cm−1. HRMS (ESI): (M + H)+ calcd for C20H20NO2, 306.1489; found, 306.1486. 3-Hydroxy-2-(5-(4-methoxyphenyl)pent-4-yn-1-yl)isoindolin-1one (1m). Pale yellow solid. Rf (hexane/EtOAc 1:1) 0.57. mp 123− 125 °C. Yield 417 mg, 65%. 1H NMR (400 MHz, CDCl3, δ): 1.81− 1.91 (m, 2 H), 2.34−2.41 (m, 2 H), 3.38−3.53 (m, 2 H), 3.76 (s, 3 H), 4.56 (J = 11.2 Hz, 1 H), 5.76 (d, J = 11.2 Hz, 1 H), 6.74 (d, J = 8.4 Hz, 2 H), 7.19 (d, J = 8.4 Hz, 2 H), 7.37 (t, J = 7.6 Hz, 1 H), 7.47−7.56 (m, 3 H). 13CNMR (150 MHz, CDCl3, δ): 17.4, 27.4, 38.8, 55.4, 81.2, 82.1, 87.6, 113.9, 115.9, 123.2, 123.5, 129.8, 131.5, 132.3, 133.0, 144.2, 159.2, 167.9. IR (KBr, neat): 3444, 2933, 1681, 1176, 1032, 746 cm−1. HRMS (ESI): (M + H)+ calcd for C20H20NO3, 322.1438; found, 322.1439. 3-Hydroxy-2-(5-(3-methoxyphenyl)pent-4-yn-1-yl)isoindolin-1one (1n). Pale yellow solid. Rf (hexane/EtOAc 1:1) 0.56. mp 120−122 °C. Yield 417 mg, 65%. 1H NMR (600 MHz, CDCl3, δ): 1.85−1.90 (m, 2 H), 2.35−2.43 (m, 2 H), 3.38−3.43 (m, 1 H), 3.46−3.51 (m, 1 H), 3.74 (s, 3 H), 4.50 (brs, 1 H), 5.76 (d, J = 11.4 Hz, 1 H), 6.79 (d, J = 8.4 Hz, 1 H), 6.82 (s, 1 H), 7.86 (d, J = 7.8 Hz, 1 H), 7.12 (t, J = 7.8 Hz, 1 H), 7.34−7.37 (m, 1 H), 7.46−7.54 (m, 3 H). 13CNMR (150 MHz, CDCl3, δ): 17.4, 27.3, 38.8, 55.4, 81.3, 82.1, 89.1, 114.4, 116.5, 123.2, 123.5, 124.2, 124.8, 129.4, 129.7, 131.5, 132.3, 144.2, 159.3, 167.9. IR (KBr, neat): 3409, 2837, 1704, 1170, 1044, 746 cm−1. HRMS (ESI): (M + H)+ calcd for C20H20NO3, 322.1438; found, 322.1444. 3-Hydroxy-2-(5-(4-nitrophenyl)pent-4-yn-1-yl)isoindolin-1-one (1o). Brown solid. Rf (hexane/EtOAc 1:1) 0.57. mp 160−162 °C. Yield 341 mg, 53%. 1H NMR (400 MHz, CDCl3, δ): 1.91−1.99 (m, 2 H), 2.45−2.52 (m, 2 H), 3.44−3.52 (m, 1 H), 3.56−3.64 (m, 1 H), 3.79 d, J = 11.6 Hz, 1 H), 5.80 (d, J = 11.2 Hz, 1 H), 7.35 (d, J = 8.8 Hz, 2 H), 7.41 (t, J = 7.6 Hz, 1 H), 7.50−7.59 (m, 3 H), 8.07 (d, J = 8.8 Hz, 2 H). 13CNMR (150 MHz, CDCl3, δ): 17.7, 27.1, 38.8, 80.1, 82.2, 95.4, 123.4, 123.5, 123.6, 130.0, 130.8, 131.6, 132.4, 132.5, 144.1, 146.8, 167.9. IR (KBr, neat): 3477, 2924, 1674, 1524, 1176, 1051, 750 cm−1. HRMS (ESI): (M + H)+ calcd for C19H17N2O4, 337.1183; found, 337.1189. 3-Hydroxy-2-(5-(thiophen-2-yl)pent-4-yn-1-yl)isoindolin-1-one (1p). Pale yellow gum. Rf (hexane/EtOAc 1:1) 0.57. Yield 297 mg, 50%. 1H NMR (600 MHz, CDCl3, δ): 1.91−1.96 (m, 2 H), 2.45−2.49 (m, 2 H), 3.49−3.52 (m, 2 H), 3.54−3.59 (m, 1 H), 5.80 (d, J = 10.8 Hz, 1 H), 6.88 (dd, J = 5.2 and 3.6 Hz, 1 H), 6.97 (dd, J = 5.2 and 8.4 Hz, 1 H), 7.14 (dd, J = 5.2 and 1.0 Hz, 1 H), 7.44 (t, J = 7.5 Hz, 1 H), 7.53 (t, J = 7.5 Hz, 1 H), 7.58 (d, J = 7.5 Hz, 1 H), 7.62 (d, J = 7.5 Hz, 1 H). 13CNMR (150 MHz, CDCl3, δ): 17.8, 27.3, 39.0, 74.6, 82.3, 93.3, 123.4, 123.5, 123.9, 126.3, 127.0, 130.0, 131.4, 131.7, 132.5, 144.1, 167.9. IR (KBr, neat): 3355, 2962,1670, 1618, 1103, 1044, 798 cm−1. HRMS (ESI): (M + H)+ calcd for C17H16NO2S, 298.0896; found, 298.0899.

3-(1-Hydroxy-3-oxo-2,3-dihydro-1H-inden-2-yl)propanenitrile (1q). Colorless solid. Rf (hexane/EtOAc 1:1) 0.52. mp 154−156; yield 218 mg, 54%. 1H NMR (600 MHz, CDCl3, δ): 2.85−2.92 (m, 2 H), 3.60−3.64 (m, 1 H), 3.82−3.87 (m, 1 H), 5.96 (d, J = 8.8 Hz, 1 H), 6.77 (d, J = 8.8 Hz, 1 H), 7.56 (t, J = 7.2 Hz, 1 H), 7.62−7.70 (m, 3 H). 13CNMR (150 MHz, CDCl3, δ): 17.6, 36.2, 82.6, 118.4, 123.4, 123.7, 129.9, 131.4, 132.6, 144.5, 167.6. IR (KBr, neat): 3432, 2852, 2249, 1668, 1105, 1058, 749 cm−1. HRMS (ESI): (M + H)+ calcd for C11H11N2O2, 203.0815; found, 203.0846. General Procedure for the Synthesis of Pyrroloisoindolone and Pyridoisoindolone. To a solution of carbinol amides (0.70 mmol) in dichloromethane (3 mL) at 0 °C was added triflic acid (0.84 mmol) dropwise under a nitrogen atmosphere. The reaction mixture was brought to room temperature, and the reaction was stirred for 12 h. After completion of the reaction, the reaction mixture was treated with saturated sodium bicarbonate solution (10 mL). The product was extracted with CH2Cl2 (2 × 15 mL), and the combined organic layer was washed with brine (10 mL). The organic layer was separated, dried over anhydrous Na2SO4, and evaporated using a rotary evaporator to obtain the crude product. The crude product was purified by silica gel column chromatography using ethyl acetate and hexane as eluents to afford the title compounds 2a−2q. (1S*,9bS*)-1-Benzoyl-2,3-dihydro-1H-pyrrolo[2,1-a]isoindol-5(9bH)-one (2a). Colorless solid. Rf (hexane/EtOAc 1:1) 0.53. mp 109−111 °C. Yield 136 mg, 70%. 1H NMR (600 MHz, CDCl3, δ): 2.50−2.57 (m, 1 H), 2.77−2.82 (m, 1 H), 3.37−3.42 (m, 1 H), 3.58− 3.62 (m, 1 H), 3.91−3.96 (m, 1 H), 5.29 (d, J = 9.6 Hz, 1 H), 7.29− 7.31 (m, 1 H), 7.42−7.47 (m, 2 H), 7.47−7.52 (m, 2 H), 7.62 (t, J = 7.2 Hz, 1 H), 7.80−7.83 (m, 1 H), 7.93 (d, J = 8.4 Hz, 2 H). 13CNMR (150 MHz, CDCl3, δ): 35.4, 41.9, 50.6, 66.0, 123.5, 124.2, 128.7, 129.0, 129.2, 132.1, 133.6, 134.2, 136.3, 145.3, 171.7, 199.2. IR (KBr, neat): 2954, 2895, 1697, 1668, 1016, 750 cm−1. HRMS (ESI): (M + H)+ calcd for C18H16NO2, 278.1176; found, 278.1172. (1S*,9bS*)-1-(4-Chlorobenzoyl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindol-5(9bH)-one (2b). Orange solid. Rf (hexane/EtOAc 1:1) 0.6. mp 152−155 °C. Yield 157 mg, 72%. 1H NMR (600 MHz, CDCl3, δ): 2.41−2.49 (m, 1 H), 2.66−2.72 (m, 1 H), 3.24−3.29 (m, 1 H), 3.49− 3.53 (m, 1 H), 3.82−3.88 (m, 1 H), 5.18 (d, J = 9.6 Hz, 1 H), 7.19− 7.21 (m, 1 H), 7.36−7.40 (m, 4 H), 7.71−7.73 (m, 1 H), 7.80 (d, J = 7.2 Hz, 2 H). 13CNMR (150 MHz, CDCl3, δ): 35.3, 41.8, 50.6, 66.0, 123.4, 124.3, 129.1, 129.5, 130.1, 132.1, 133.6, 134.5, 140.8, 145.1, 171.6, 198.0. IR (KBr, neat): 2925, 2895, 1695, 1677, 1271, 1090, 749 cm−1. HRMS (ESI): (M + H)+ calcd for C18H15ClNO2, 312.0786; found, 312.0782. (1S*,9bS*)-1-(4-Bromobenzoyl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindol-5(9bH)-one (2c). Pale yellow solid. Rf (hexane/EtOAc 1:1) 0.57. mp 162−164 °C. Yield 181 mg, 73%. 1H NMR (600 MHz, CDCl3, δ): 2.49−2.57 (m, 1 H), 2.73−2.79 (m, 1 H), 3.30−3.35 (m, 1 H), 3.58−3.62 (m, 1 H), 3.91−3.96 (m, 1 H), 5.26 (d, J = 9.6 Hz, 1 H), 7.27−7.29 (m, 1 H), 7.45−7.47 (m, 2 H), 7.64 (d, J = 8.4 Hz, 2 H), 7.79 (d, J = 8.4 Hz, 2 H), 7.80−7.82 (m, 1 H). 13CNMR (150 MHz, CDCl3, δ): 35.3, 41.9, 50.6, 66.0, 123.4, 124.3, 129.2, 129.6, 130.2, 132.1, 132.5, 133.6, 135.0, 145.1, 171.6, 198.2. IR (KBr, neat): 2924, 2846, 1696, 1673, 1071, 752 cm−1. HRMS (ESI): (M + H)+ calcd for C18H15BrNO2, 356.0281; found, 356.0268 (79Br). (1S*,9bS*)-1-(4-Fluorobenzoyl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindol-5(9bH)-one (2d). Colorless solid. Rf (hexane/EtOAc 1:1) 0.57. mp 139−141 °C. Yield 134 mg, 65%. 1H NMR (600 MHz, CDCl3, δ): 2.52−2.59 (m, 1 H), 2.76−2.82 (m, 1 H), 3.33−3.38 (m, 1 H), 3.59−3.64 (m, 1 H), 3.92−3.97 (m, 1 H), 5.26 (d, J = 9.6 Hz, 1 H), 7.18 (t, J = 8.4 Hz, 2 H), 7.28−7.31 (m, 1 H), 7.46−7.49 (m, 2 H), 7.80−7.84 (m, 1 H), 7.96−7.99 (m, 2 H). 13CNMR (150 MHz, CDCl3, δ): 35.3, 41.9, 50.6, 66.0, 116.3 (d, J = 21.9 Hz), 123.4, 124.3, 129.1, 131.4 (d, J = 9.5 Hz), 132.1, 132.7, 133.6, 166.4 (d, J = 255.2 Hz), 171.6, 197.6; 19F NMR (376 MHz, CDCl3/C6F6, δ): 58.5. IR (KBr, neat): 2931, 2889, 1697, 1677, 1016, 752 cm−1. HRMS (ESI): (M + H)+ calcd for C18H15FNO2, 296.1081; found, 296.1061. (1S*,9bS*)-1-(4-Methylbenzoyl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindol-5(9bH)-one (2e). Brown solid. Rf (hexane/EtOAc 1:1) 0.54. mp 125−128 °C. Yield 163 mg, 80%. 1H NMR (600 MHz, CDCl3, δ): 6182

DOI: 10.1021/acs.joc.8b00440 J. Org. Chem. 2018, 83, 6178−6185

Note

The Journal of Organic Chemistry

(1S*,10bS*)-1-(4-Methoxybenzoyl)-1,3,4,10b-tetrahydropyrido[2,1-a]isoindol-6(2H)-one (2m). Pale yellow solid. Rf (hexane/EtOAc 7:3) 0.52. mp 160−162 °C. Yield 195 mg, 87%. 1H NMR (600 MHz, CDCl3, δ): 1.61−1.67 (m, 1 H), 1.74−1.78 (m, 1 H), 2.13−2.19 (m, 1 H), 2.20−2.26 (m, 1 H), 3.05 (dt, J = 12.6 and 3.6 Hz, 1 H), 3.83 (s, 3 H), 4.29−4.33 (m, 1 H), 4.56−4.60 (m, 2 H), 6.86 (d, J = 8.4 Hz, 2 H), 7.22 (d, J = 7.2 Hz, 1 H), 7.31−7.38 (m, 2 H), 7.73 (d, J = 8.4 Hz, 2 H), 7.86 (d, J = 7.2 Hz, 1 H). 13CNMR (150 MHz, CDCl3, δ): 20.2, 27.3, 39.4, 41.4, 55.7, 59.3, 114.0, 120.9, 123.8, 128.2, 129.8, 130.4, 131.0, 134.1, 143.6, 163.7, 167.1, 196.9. IR (KBr, neat): 2928, 2855, 1675, 1670, 1174, 1027, 732 cm−1. HRMS (ESI): (M + H)+ calcd for C20H20NO3, 322.1443; found, 322.1442. (1S*,10bS*)-1-(3-Methoxybenzoyl)-1,3,4,10b-tetrahydropyrido[2,1-a]isoindol-6(2H)-one (2n). Pale yellow solid. Rf (hexane/EtOAc 7:3) 0.51. mp 151−153 °C. Yield 195 mg, 85%. 1H NMR (600 MHz, CDCl3, δ): 1.62−1.67 (m, 1 H), 1.70−1.79 (m, 1 H), 2.15−2.21 (m, 1 H), 2.23−2.28 (m, 1 H), 3.06 (dt, J = 13.2 and 4.2 Hz, 1 H), 3.75 (s, 3 H), 4.33−4.36 (m, 1 H), 4.57 (dd, J = 13.2 and 4.8 Hz, 1 H), 4.60 (d, J = 4.2 Hz, 1 H), 7.04−7.07 (m, 1 H), 7.16−7.19 (m, 1 H), 7.23 (d, J = 7.2 Hz, 1 H), 7.30−7.34 (m, 2 H), 7.35−7.38 (m, 2 H), 7.86 (d, J = 7.2 Hz, 1 H). 13CNMR (150 MHz, CDCl3, δ): 20.1, 27.1, 39.3, 41.9, 55.6, 59.2, 112.3, 119.8, 120.4, 121.0, 123.7, 128.2, 129.8, 131.0, 134.0, 138.1, 143.5, 160.1, 167.0, 198.2. IR (KBr, neat): 2937, 2859, 1681, 1675, 1171, 1040, 744 cm−1. HRMS (ESI): (M + H)+ calcd for C20H20NO3, 322.1443; found, 322.1419. (1S*,10bS*)-1-(Thiophene-2-carbonyl)-1,3,4,10btetrahydropyrido[2,1-a]isoindol-6(2H)-one (2p). Colorless solid. Rf (hexane/EtOAc 7:3) 0.52. mp 183−185 °C. Yield 125 mg, 60%. 1H NMR (600 MHz, CDCl3, δ): 1.61 (dt, J = 12.6 and 4.8 Hz, 1 H), 1.93 (dt, J = 12.6 and 3.0 Hz, 1 H), 1.94−1.98 (m, 1 H), 2.28 (dd, J = 12.6 and 3.0 Hz, 1 H), 2.96−3.06 (m, 2 H), 4.58 (dd, J = 13.2 and 4.8 Hz, 1 H), 4.90 (d, J = 10.2 Hz, 1 H), 7.12 (dt, J = 4.8 and 4.2 Hz, 1 H), 7.21 (d, J = 7.2 Hz, 1 H), 7.36 (t, J = 7.2 Hz, 1 H), 7.42 (t, J = 7.2 Hz, 1 H), 7.59 (dd, J = 4.2 and 1.2 Hz, 1 H), 7.72 (dd, J = 4.8 and 1.2 Hz, 1 H), 7.86 (d, J = 7.2 Hz, 1 H). 13CNMR (150 MHz, CDCl3, δ): 25.1, 30.0, 39.2, 52.1, 59.5, 123.2, 123.9, 128.7, 128.8, 131.6, 132.4, 133.0, 135.4, 143.5, 144.4, 166.5, 194.2. IR (KBr, neat): 2925, 2857, 1674, 1647, 1091, 752 cm−1. HRMS (ESI): (M + H)+ calcd for C17H16NO2S, 298.0896; found, 298.0899. 1,3,4,10b-Tetrahydropyrimido[2,1-a]isoindole-2,6-dione (2q). Colorless solid. Rf (CHCl3/MeOH 9:1) 0.56. mp 214−216 °C. Yield 92 mg, 65%. 1H NMR (600 MHz, CDCl3, δ): 2.53−2.57 (m, 2 H), 3.44−3.48 (m, 1 H), 4.44−4.49 (m, 1 H), 5.82 (s, 1 H), 7.55 (t, J = 7.2 Hz, 1 H), 7.62 (t, J = 7.2 Hz, 1 H), 7.67 (d, J = 7.5 Hz, 1 H), 7.85 (d, J = 7.5 Hz, 1 H), 8.81 (s, 1 H). 13CNMR (150 MHz, CDCl3, δ): 31.1, 35.3, 66.8, 123.0, 124.3, 130.3, 131.7, 132.9, 142.2, 167.5, 170.7. IR (KBr, neat): 2924, 2853, 1670, 1537, 1155, 1082, 731 cm−1. HRMS (ESI): (M + H)+ calcd for C11H11N2O2, 203.0815; found, 203.0806. Procedure for the Reaction of 1f in the Presence of Dry Methanol. To a solution of 3-hydroxy-2-(4-(o-tolyl)but-3-yn-1yl)isoindolin-1-one (1f) (194 mg, 0.70 mmol) in dry dichloromethane (3 mL), dry methanol (1 mL), and molecular sieves 4 Å at 0 °C was added triflic acid (68 μL, 0.77 mmol, 1.2 equiv) dropwise under a nitrogen atmosphere. The reaction mixture was brought to room temperature, and the reaction was stirred for 12 h. After completion of the reaction, the solvents were removed under reduced pressure, and the reaction mixture was diluted with ethyl acetate and then treated with saturated sodium bicarbonate solution (10 mL). The product was extracted with ethyl acetate (2 × 15 mL), and the combined organic layer was washed with brine. The organic layer was separated, dried over anhydrous Na2SO4, and evaporated using a rotary evaporator to obtain the crude product. The crude product was purified by silica gel column chromatography using ethyl acetate and hexane as eluents to afford (E)-1-(methoxy(o-tolyl)methylene)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindol-5(9bH)-one (4) as a reddish liquid. Rf (hexane/ EtOAc, 7:3) 0.78. Yield 75 mg, 62%. 1H NMR (400 MHz, CDCl3, δ): 2.33 (s, 3 H), 2.80−2.96 (m, 2 H), 2.92 (s, 3 H), 3.51−3.59 (m, 1 H), 4.02−4.10 (m, 1 H), 6.12 (s, 1 H), 7.05−7.16 (m, 3 H), 7.31 (d, J = 7.5 Hz, 1 H), 7.51−7.61 (m, 3 H), 7.85 (d, J = 7.5 Hz, 1 H). 13CNMR

2.34 (s, 3 H), 2.40−2.48 (m, 1 H), 2.66−2.72 (m, 1 H), 3.26−3.32 (m, 1 H), 3.48−3.52 (m, 1 H), 3.82−3.87 (m, 1 H), 5.19 (d, J = 9.6 Hz, 1 H), 7.19−7.22 (m, 3 H), 7.35−7.37 (m, 2 H), 7.70−7.72 (m, 1 H), 7.74 (d, J = 8.4 Hz, 2 H). 13CNMR (150 MHz, CDCl3, δ): 21.9, 35.4, 41.9, 50.4, 66.0, 123.5, 124.1, 128.8, 128.9, 129.8, 132.0, 133.6, 133.8, 145.2, 145.3, 171.6, 198.7. IR (KBr, neat): 2931, 2890, 1697, 1672, 1182, 752 cm−1. HRMS (ESI): (M + H)+ calcd for C19H18NO2, 292.1332; found, 292.1338. (1S*,9bS*)-1-(2-Methylbenzoyl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindol-5(9bH)-one (2f). Pale yellow solid. Rf (hexane/EtOAc 1:1) 0.53. mp 98−100 °C. Yield 153 mg, 75%. 1H NMR (600 MHz, CDCl3, δ): 2.47−2.53 (m, 1 H), 2.58 (s, 3 H), 2.65−2.70 (m, 1 H), 3.28−3.33 (m, 1 H), 3.54−3.60 (m, 1 H), 3.85−3.91 (m, 1 H), 5.21 (d, J = 9.0 Hz, 1 H), 7.24 (t, J = 7.2 Hz, 1 H), 7.31 (d, J = 7.8 Hz, 1 H), 7.35 (d, J = 7.2 Hz, 1 H), 7.41 (t, J = 7.2 Hz, 1 H), 7.44−7.49 (m, 2 H), 7.51 (d, J = 7.8 Hz, 1 H), 7.79−7.81 (m, 1 H). 13CNMR (150 MHz, CDCl3, δ): 21.7, 34.9, 41.8, 53.1, 66.1, 123.6, 124.3, 126.2, 129.0, 129.1, 132.1, 132.3, 132.5, 133.7, 137.0, 139.0, 145.3, 171.7, 202.6. IR (KBr, neat): 2926, 2895, 1697, 1674, 1143, 1014, 751 cm−1. HRMS (ESI): (M + H)+ calcd for C19H18NO2, 292.1332; found, 292.1339. (1S*,9bS*)-1-(4-Methoxybenzoyl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindol-5(9bH)-one (2g). Brown solid. Rf (hexane/EtOAc 1:1) 0.43. mp 157−159 °C. Yield 183 mg, 85%. 1H NMR (600 MHz, CDCl3, δ): 2.51−2.59 (m, 1 H), 2.73−2.78 (m, 1 H), 3.31−3.37 (m, 1 H), 3.57− 3.62 (m, 1 H), 3.88 (s, 3 H), 3.90−3.95 (m, 1 H), 5.27 (d, J = 9.6 Hz, 1 H), 6.95 (d, J = 9.0 Hz, 2 H), 7.26−7.29 (m, 1 H), 7.44−7.46 (m, 2 H), 7.81 (d, J = 7.2 Hz, 1 H), 7.90 (d, J = 9.0 Hz, 2 H). 13CNMR (150 MHz, CDCl3, δ): 35.4, 41.9, 50.2, 55.8, 66.2, 114.3, 123.5, 124.2, 129.0, 129.4, 131.1, 132.0, 133.7, 145.4, 164.4, 171.7, 197.5. IR (KBr, neat): 2923, 2842, 1697, 1667, 1172, 1020, 751 cm−1. HRMS (ESI): (M + H)+ calcd for C19H18NO3, 308.1281; found, 308.1263. (1S*,10bS*)-1-Benzoyl-1,3,4,10b-tetrahydropyrido[2,1-a]isoindol-6(2H)-one (2j). Pale yellow solid. Rf (hexane/EtOAc 7:3) 0.53. mp 213-215 °C. Yield 153 mg, 75%. 1H NMR (600 MHz, CDCl3, δ): 1.64−1.67 (m, 1 H), 1.74−1.79 (m, 1 H), 2.15−2.21 (m, 1 H), 2.24−2.27 (m, 1 H), 3.06 (dt, J = 13.2 and 4.2 Hz, 1 H), 4.34− 4.37 (m, 1 H), 4.57−4.62 (m, 2 H), 7.22 (d, J = 7.2 Hz, 1 H), 7.32 (t, J = 7.2 Hz, 1 H), 7.33−7.41 (m, 3 H), 7.72 (d, J = 8.4 Hz, 2 H), 7.88 (d, J = 7.2 Hz, 2 H). 13CNMR (150 MHz, CDCl3, δ): 20.2, 27.1, 39.4, 41.8, 59.2, 120.9, 123.8, 128.1, 128.3, 128.9, 131.0, 133.3, 134.1, 136.8, 143.5, 167.1, 198.4. IR (KBr, neat): 2924, 2855, 1681, 1678, 1117, 1025, 725 cm−1. HRMS (ESI): (M + H)+ calcd for C19H18NO2, 292.1332; found, 292.1333. (1S*,10bS*)-1-(4-Bromobenzoyl)-1,3,4,10b-tetrahydropyrido[2,1a]isoindol-6(2H)-one (2k). Pale yellow solid. Rf (hexane/EtOAc 7:3) 0.52. mp 217−220 °C. Yield 207 mg, 80%. 1H NMR (600 MHz, CDCl3, δ): 1.65−1.68 (m, 1 H), 1.70−1.77 (m, 1 H), 2.14−2.23 (m, 2 H), 3.05 (dt, J = 13.2 and 4.2 Hz, 1 H), 4.29−4.32 (m, 1 H), 4.57 (dd, J = 13.2 and 4.8 Hz, 1 H), 4.61 (d, J = 4.8 Hz, 1 H), 7.21 (d, J = 7.2 Hz, 1 H), 7.33 (t, J = 7.2 Hz, 1 H), 7.38 (t, J = 7.2 Hz, 1 H), 7.52 (d, J = 8.4 Hz, 2 H), 7.58 (d, J = 8.4 Hz, 2 H), 7.86 (d, J = 7.2 Hz, 1 H). 13 CNMR (150 MHz, CDCl3, δ): 20.1, 27.0, 39.3, 41.8, 59.1, 120.9, 123.8, 128.3, 128.5, 129.6, 131.1, 132.2, 134.0, 135.5, 143.3, 167.0, 197.4. IR (KBr, neat): 2925, 2856, 1680, 1677, 1261, 1070, 689 cm−1. HRMS (ESI): (M + H)+ calcd for C19H17BrNO2, 370.0437; found, 370.0457 (79Br). (1S*,10bS*)-1-(4-Methylbenzoyl)-1,3,4,10b-tetrahydropyrido[2,1a]isoindol-6(2H)-one (2l). Colorless solid. Rf (hexane/EtOAc 7:3) 0.51. mp 202−204 °C. Yield 181 mg, 85%. 1H NMR (600 MHz, CDCl3, δ): 1.62−1.67 (m, 1 H), 1.70−1.78 (m, 1 H), 2.13−2.25 (m, 1 H), 2.22−2.26 (m, 1 H), 2.37 (s, 3 H), 3.05 (dt, J = 13.2 and 4.2 Hz, 1 H), 4.30−4.34 (m, 1 H), 4.56−4.60 (m, 2 H), 7.19 (d, J = 8.4 Hz, 1 H), 7.22 (d, J = 7.2 Hz, 2 H), 7.32 (t, J = 7.2 Hz, 1 H), 7.37 (t, J = 7.2 Hz, 1 H), 7.64(d, J = 8.4 Hz, 2 H), 7.58 (d, J = 7.2 Hz, 1 H). 13CNMR (150 MHz, CDCl3, δ): 20.2, 21.8, 27.2, 39.4, 41.6, 59.3, 120.9, 123.8, 128.2, 128.24, 129.6, 131.0, 134.1, 134.3, 143.6, 144.1, 167.1, 197.9. IR (KBr, neat): 2928, 2853, 1678, 1672, 1092, 739 cm−1. HRMS (ESI): (M + H)+ calcd for C20H20NO2, 306.1489; found, 306.1487. 6183

DOI: 10.1021/acs.joc.8b00440 J. Org. Chem. 2018, 83, 6178−6185

Note

The Journal of Organic Chemistry (100 MHz, CDCl3, δ): 19.5, 20.8, 38.8, 49.5, 81.2, 86.9, 90.8, 123.3, 123.6, 123.7, 125.6, 128.0, 129.5, 130.2, 132.1, 132.3, 133.1, 140.2, 140.6, 167.9. IR (KBr, neat): 2925, 2855, 1686, 1189, 1103, 1019, 732 cm−1. HRMS (ESI): (M + H)+ calcd for C20H20NO2, 306.1489; found, 306.1516. General Procedure for the Treatment of 2b and 2c with KOH. To a stirred solution of 2b and 2c (0.36 mmol) in dry methanol (3 mL) at 0 °C was added a solution of potassium hydroxide (0.72 mmol) in methanol dropwise under a nitrogen atmosphere. The reaction mixture was brought to room temperature, and the reaction was stirred for 12 h. After completion of the reaction, the reaction mixture was evacuated under reduce pressure. The product was extracted with ethyl acetate (2 × 15 mL), and the combined organic layer was washed with brine (10 mL). The organic layer was separated, dried over anhydrous Na2SO4, and evaporated using a rotary evaporator to obtain the crude product. The crude product was purified by silica gel column chromatography using ethyl acetate and hexane as eluents to give diastereomeric products 2b, 3b and 2c, 3b with a diastreromeric ratio of 77:23 and 71:29, respectively. (1S*,9bS*)-1-(4-Chlorophenyl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindol-5(9bH)-one (3b). Pale yellow semi solid. Rf (hexane/EtOAC 3:2) 0.42. Yield 7 mg, 25%. 1H NMR (600 MHz, CDCl3, δ): 2.56− 2.62 (m, 1 H), 2.64−2.68 (m, 1 H), 3.51−3.55 (m, 1 H), 4.10−4.14 (m, 1 H), 4.38 (t, J = 6.2 Hz, 1 H), 5.10 (d, J = 6.1 Hz, 1 H), 6.96 (d, J = 7.6 Hz, 1 H), 7.17 (t, J = 7.6 Hz, 1 H), 7.31−7.34 (m, 3 H), 7.57 (d, J = 7.6 Hz, 2 H), 7.72 (d, J = 7.6 Hz, 1 H). 13CNMR (150 MHz, CDCl3, δ): 33.2, 42.2, 44.5, 66.8, 123.4, 124.1, 128.9, 129.1, 129.5, 131.2, 134.9, 136.0, 139.9, 141.8, 171.6, 198.2. IR (KBr, neat): 2923, 2855, 1672, 1589, 1091, 1033, 801 cm−1. HRMS (ESI): (M + H)+ calcd for C18H15ClNO2, 312.0786; found, 312.0812. (1S*,9bS*)-1-(4-Bromophenyl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindol-5(9bH)-one (3c). Pale yellow solid. Rf (hexane/EtOAc 3:2) 0.43. mp 155−157 °C. Yield 5 mg, 23%. 1H NMR (600 MHz, CDCl3, δ): 2.59−2.64 (m, 1 H), 2.66−2.70 (m, 1 H), 3.52−3.56 (m, 1 H), 4.12−4.17 (m, 1 H), 4.38 (t, J = 6.2 Hz, 1 H), 5.12 (d, J = 6.8 Hz, 1 H), 6.98 (d, J = 7.6 Hz, 1 H), 7.20 (t, J = 7.6 Hz, 1 H), 7.33 (t, J = 7.6 Hz, 1 H), 7.48−7.52 (m, 4 H), 7.74 (d, J = 7.6 Hz, 1 H). 13CNMR (150 MHz, CDCl3, δ): 33.2, 42.2, 44.5, 66.8, 123.4, 124.1, 128.7, 128.9, 129.6, 131.2, 132.1, 134.9, 136.4, 141.8, 171.6, 198.4. IR (KBr, neat): 2924, 2855, 1684, 1585, 1091, 1070, 743 cm−1. HRMS (ESI): (M + H)+ calcd for C18H15BrNO2, 356.0281; found, 356.0283.

■

India for financial support. The authors are also thankful to the Central Instrument Facility (CIF) of IIT Guwahati for NMR facilities.

■

(1) Honma, T.; Yoshizumi, T.; Hashimoto, N.; Hayashi, K.; Kawanishi, N.; Fukasawa, K.; Takaki, T.; Ikeura, C.; Ikuta, M.; Suzuki-Takahashi, I.; Hayama, T.; Nishimura, S.; Morishima, H. A Novel Approach for the Development of Selective Cdk4 Inhibitors: Library Design Based on Locations of Cdk4 Specific Amino Acid Residues. J. Med. Chem. 2001, 44, 4628−4640. (2) (a) Boulahjar, R.; Ouach, A.; Matteo, C.; Bourg, S.; Ravache, M.; Guével, R. L.; Marionneau, S.; Oullier, T.; Lozach, O.; Meijer, L.; Guguen-Guillouzo, C.; Lazar, S.; Akssira, M.; Troin, Y.; Guillaumet, G.; Routier, S. Novel Tetrahydropyrido[1,2-a]isoindolone Derivatives (Valmerins): Potent Cyclin-Dependent Kinase/Glycogen Synthase Kinase 3 Inhibitors with Antiproliferative Activities and Antitumor Effects in Human Tumor Xenografts. J. Med. Chem. 2012, 55, 9589− 9606. (b) Chiurato, M.; Routier, S.; Troin, Y.; Guillaumet, G. New Efficient Route to Fused Aryltetrahydroindolizinones via N-Acyliminium Intermediates. Eur. J. Org. Chem. 2009, 2009, 3011−3021. (3) Luci, D. K.; Lawson, E. C.; Ghosh, S.; Kinney, W. A.; Smith, C. E.; Wang, J.; Qi, Y.; Minor, L. K.; Maryanoff, B. E. Generation of novel, potent urotensin-II receptor antagonists by alkylation− cyclization of isoindolinone C3-carbanions. Tetrahedron Lett. 2009, 50, 4958−4961. (4) Oukoloff, K.; Buron, F.; Routier, S.; Jean, L.; Renard, P.-Y. Synthetic Route to Rare Isoindolones Derivatives. Eur. J. Org. Chem. 2015, 2015, 2450−2456 and references cited therein.. (5) For a recent review, see Wu, P.; Nielsen, T. E. Scaffold Diversity from N-Acyliminium Ions. Chem. Rev. 2017, 117, 7811−7856. (6) (a) Othman, R. B.; Bousquet, T.; Fousse, A.; Othman, M.; Dalla, V. Toward Improving the Chemistry of N-Acyliminium Ions: Nucleophilic Substitution Reactions of Pyrrolidinone Derivatives with Trialkylsilyl Nucleophiles Catalyzed by Triisopropylsilyltrifluoromethane Sulfonate (TIPSOTf). Org. Lett. 2005, 7, 2825−2828. (b) Morgan, I. R.; Yazici, A.; Pyne, S. G.; Skelton, B. W. Diastereoselective Ritter Reactions of Chiral Cyclic N-Acyliminium Ions: Synthesis of Pyrido- and Pyrrolo[2,3-d]oxazoles and 4-Hydroxy5-N-acylaminopyrrolidines and 5-Hydroxy-6-N-acylaminopiperidines. J. Org. Chem. 2008, 73, 2943−2946. (c) Sun, H.; Martin, C.; Kesselring, D.; Keller, R.; Moeller, K. D. Building Functionalized Peptidomimetics: Use of Electroauxiliaries for Introducing NAcyliminium Ions into Peptides. J. Am. Chem. Soc. 2006, 128, 13761−13771. (7) (a) Knowles, R. R.; Lin, S.; Jacobsen, E. N. Enantioselective Thiourea-Catalyzed Cationic Polycyclizations. J. Am. Chem. Soc. 2010, 132, 5030−5032. (b) Dijkink, J.; Speckamp, W. N. Biomimetic heterocyclization of aryl olefins. One-step formation of two carboncarbon bonds. Tetrahedron 1978, 34, 173−178. (c) Schoemaker, H. E.; Speckamp, W. N. Stereocontrolled synthesis of functionalized 1azaspirans. Efficient synthesis of perhydrohistrionicotoxin. Tetrahedron 1980, 36, 951−958. (8) (a) Van Brabandt, W.; De Kimpe, N. Diastereoselective Ring Expansion of β-Lactams toward γ-Lactams via N-Acyliminium Intermediates. J. Org. Chem. 2005, 70, 3369−3374. (b) Van Brabandt, W.; De Kimpe, N. Electrophile-Induced Ring Expansions of β-Lactams toward γ-Lactams. J. Org. Chem. 2005, 70, 8717−8722. (c) Dekeukeleire, S.; D’hooghe, M.; De Kimpe, N. Diastereoselective Synthesis of Bicyclic γ-Lactams via Ring Expansion of Monocyclic βLactams. J. Org. Chem. 2009, 74, 1644−1649. (9) Chiurato, M.; Routier, S.; Troin, Y.; Guillaumet, G. New efficient route to fused aryltetrahydroindolizinones via N-acyliminium intermediates. Eur. J. Org. Chem. 2009, 2009, 3011−3021. (10) Welch, W. M. Synthesis of 4,N-diaryl-2-methyl-5-oxo1,4,5,6,7,8-hexahydroquinoline-3-carboxamides. J. Org. Chem. 1982, 47, 886−888.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00440. 1 H and 13C NMR spectra of all of the new compounds, 19 F NMR spectra of 1d and 2d, NOE spectra of compound 4, and X-ray crystallographic data of compound 2b (PDF) HRMS spectra of all of the new compounds (PDF) X-ray crystallographic data for compound 2b (CIF)

■

REFERENCES

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]; Fax: +91-361-2690762. ORCID

Anil K. Saikia: 0000-0002-3721-8156 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS M.D. gratefully acknowledges the ndian Institute of Technology Guwahati for his fellowship. The authors are grateful to the Council of Scientific and Industrial Research (CSIR), New Delhi (Grant 02/0159/13/EMR-II), and CoE, MHRD, Govt of 6184

DOI: 10.1021/acs.joc.8b00440 J. Org. Chem. 2018, 83, 6178−6185

Note

The Journal of Organic Chemistry (11) Kim, S. H.; Kim, H. G.; Choo, H.; Cha, J. H.; Pae, A. N.; Koh, H. Y.; Chung, B. Y.; Cho, Y. S. N-Acyliminium ion cyclizations of trimethylsilylmethylallenes. Tetrahedron Lett. 2006, 47, 6353−6356. (12) Debien, L.; Braun, M.-G.; Quiclet-Sire, B.; Zard, S. Z. Tri- and Tetrasubstituted Functionalized Vinyl Sulfides by Radical Allylation. Org. Lett. 2013, 15, 6250−6253. (13) Sai, K. K. S.; O’Connor, M. J.; Klumpp, D. A. Aza-Nazarov cyclization cascades. Tetrahedron Lett. 2011, 52, 2195−2198. (14) (a) Indukuri, K.; Unnava, R.; Deka, M. J.; Saikia, A. K. Stereoselective Synthesis of Amido and Phenyl Azabicyclic Derivatives via a Tandem Aza Prins-Ritter/Friedel-Crafts Type Reaction of Endocyclic N-Acyliminium Ions. J. Org. Chem. 2013, 78, 10629− 10641. (b) Saikia, A. K.; Indukuri, K.; Das, J. Stereoselective synthesis of O-tosyl azabicyclic derivatives via aza Prins reaction of endocyclic N-acyliminium ions: application to the total synthesis of (±)-epiindolizidine 167B and 209D. Org. Biomol. Chem. 2014, 12, 7026− 7035. (15) The crystallographic data for the compound 7b has been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 1585418. (16) Zamilpa, A.; Herrera-Ruiz, M.; Del Olmo, E.; López-Pérez, L. J.; Tortoriello, J.; San Feliciano, A. [1,3]Diazaheterofused isoindolol derivatives displaying anxiolytic-like effects on mice. Bioorg. Med. Chem. Lett. 2007, 17, 4016−4021. (17) Del Olmo, E.; Barboza, B.; Ybarra, I. M.; López-Pérez, L. J.; Carrón, R.; Sevilla, A. M.; Boselli, C.; San Feliciano, A. Vasorelaxant activity of phthalazinones and related compounds. Bioorg. Med. Chem. Lett. 2006, 16, 2786−2790. (18) Del Olmo, E.; Armas, G. M.; Ybarra, I. M.; López, L. J.; Oporto, P.; Giménez, A.; Deharo, E.; San Feliciano, A. The imidazo[2,1a]isoindole system. A new skeletal basis for antiplasmodial compounds. Bioorg. Med. Chem. Lett. 2003, 13, 2769−2772. (19) Nesmeřaḱ , K.; Pelouchová, H.; Všetečka, V.; Nemec, I.; Gabriel, J. Antifungal effects of new heterocyclic compounds, 6H-pyrimido[2,1a]isoindole derivatives. Folia Microbiol. 1998, 43, 39−41. (20) Gogoi, P.; Das, V. K.; Saikia, A. K. Diastereoselective Synthesis of Substituted Tetrahydrofurans via Prins Cyclization of Enol Ethers. J. Org. Chem. 2014, 79, 8592−8598.

6185

DOI: 10.1021/acs.joc.8b00440 J. Org. Chem. 2018, 83, 6178−6185