Stereoselective Synthesis of Pyrroloisoindolone and

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Stereoselective Synthesis of Pyrroloisoindolone and Pyridoisoindolone via aza-Prins Cyclization of Endocyclic N-Acyliminium Ions Malay Das, and Anil K. Saikia J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00440 • Publication Date (Web): 01 May 2018 Downloaded from http://pubs.acs.org on May 1, 2018

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The Journal of Organic Chemistry

Stereoselective Synthesis of Pyrroloisoindolone and Pyridoisoindolone via aza-Prins Cyclization of Endocyclic NAcyliminium Ions

Malay Das and Anil K. Saikia* Department of Chemistry Indian Institute of Technology Guwahati, Guwahati - 781039, India. Fax: +91-361-2690762. e-mail: [email protected] RECEIVED DATE (will be automatically inserted after manuscript is accepted).

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. Pyrroloisoindolone 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 inhibitor1 whereas tetrahydropyrido[1,2a]isoindolone derivatives (valmerin vitamins) are potent cyclin-dependent kinase/glycogen synthase kinase-3 inhibitors and also exhibit antitumor activities.2 On the other hand,

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pyrroloisoindolone derivatives are urotensin-II receptor antagonists.3 Apart from their existence in biological active moleculaes, 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 recent past. N-Acyliminium ions are versatile reaction intermediates in construction of N-heterocyclic scaffolds. Due to the presence of carbonyl group the Nacyliminium ions are highly reactive electrophiles5 and several groups have utilized this intermediate for the construction of a range of structurally diverse compounds via intra- and inter-molecular 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 β-hydroxy lactones via acyl iminium ions,9

carboxybenzaldehyde,10

trimethylsilylmethylallenes,11

N-acyliminium

cyclization

of

ion

cyclizations

2-bromo-3-nitrobenzoic

of acid,4

nitrophthalimide,2 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 aza-Prins cyclization reaction of Nacyliminium 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 derivatives having 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 oC for 12h but the reaction resulted in a mixture of complex products. Other Lewis acid such as indium chloride (InCl3) (Table 1, entry 2) also produced complex products while ferric chloride (FeCl3),

indium(III)

trifluoromethanesulfonate

(In(OTf)3)


and

trimethylsilyl

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trifluoromethanesulfonate (TMSOTf) (Table 1, entries 3-5) gave 3-hydroxy-2-(4-phenylbut3-yn-1-yl)isoindolin-1-one 2a as a single diastereomer in 47, 40, and 60% yields, respectively. Brønsted acid, trifluoroacetic acid (Table 1, entry 6) also found to be effective Table 1. Optimization of the reaction

for the reaction but with a lower yield. Trifluoromethanesulfonic acid (triflic acid) (Table 1, entry 7) in dichloromethane under similar conditions gave 70% yield. The same reaction under catalytic amount of triflic acid gave only 25% yield even after exposure to long duration of time (Table 1, entry 8). Reaction in presence of molecular sieves (Table 1, entry 9) gave 65% yield. Other solvents such as acetonitrile and toluene (Table 1, entries 10-11) are



found to be ineffective and produced the mixture of complex products. Other Bronsted acid p-toluenesulfonic acid (p-TsOH) (Table 1, entry 12) did not give desired product but starting material was recovered after prolonged reaction for 24h. With this optimum reaction conditions in hand, the scope of the reaction was investigated with a variety of substrates 1a-n (Table 2), which were prepared from literature procedure.14 Table 2. Synthesis of pyrrolo- and pyridoisoindolone via aza-Prins cyclization reaction


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aYield

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



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It was observed from Table 2 that the success of the reaction depend on the substituents in 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 moderately electron withdrawing groups in the aromatic ring (Table 2, entries 24). On contrary the terminal alkyne (Table 2, entry 8) and alkyl substituted alkyne (Table 2, entry 9) failed to give desired product; instead starting material were recovered in 95% yield. This might be due to the instability of 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 follows the similar trends in terms of reactivity like substrates 1a-h. Highly electron withdrawing nitro group on aromatic ring of the substrate 1o reduces the nucleophilicity of the alkyne group which is responsible for recovery of the starting material. Ortho- and meta-substituted aromatic moiety in the alkyne side chain did not affect the rate of the reaction (Table 2, entries 6, 13). Heteroaryl substituent in the alkyne side (Table 2, entry 15) also worked well producing compound 2p in 60% yield. The structure of the all compounds was determined with the help of 1H and

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C 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 substrate1q under similar reaction conditions produced pyrimidoisoindole 2q in 65% yield (Scheme 1). Importantly, pyrimido[2,1- a]isoindoles Scheme 1. Synthesis of pyrimidoisoindole


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exhibit many biological properties namely anxiolytic,16 vasorelaxant,17 antiplasmodial18 and antifungal19 activities. The mechanism of the reaction can be explained as follows. Trifluoromethanesulphonic acid generates N-acyliminium ion A from carbinol 1, which after 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 gives thermodynamically more stable tricyclic azo-compounds 2 in which 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 (Scheme 2). Another possibility is the formation of most stable compound 2 by equilibration of initially formed compounds 2 and 3 via enolization under acidic conditions. Scheme 2. Plausible reaction mechanism

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 62% yield, the E geometry of which was determined by nOe experiment (see SI) (Scheme 3). In order to prove that the product is the result of



Scheme 3: Trapping of carbocation B with methanol

thermodynamically controlled reaction, compounds 2b and 2c were treated with KOH in dry methanol (equation 1) and it was observed that the ratio of diastereomers 2b:3b and 2c:3c were 77:23 and 71:29 respectively (Scheme 4). Importantly, when two diastereomers 2b and 3b were treated with triflic acid under the optimized reaction conditions there was no change in the ratio of diastereomers. 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. Scheme 4: Reaction of 2b-c with KOH

In conclusion, we have developed a methodology for the synthesis of substituted pyrroloisoindolone and pyridoiso-indolone via aza-Prins cyclization of endocyclic Nacyliminium ions. The reaction is atom economic and good yields are achieved with high


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diastereoselectivity. The reaction can also be extended for the synthesis of pyrimidoisoindole in good yield. Experimental Section: General Information: All 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 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 1H (600, 400 MHz) or C (150, 100 MHz). Chemical shifts (δ) are reported in ppm and spin-spin coupling

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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 oC 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 (2x20 mL). The organic phase was washed with brine, dried over anhydrous Na2SO4. Evaporation of the solvent gave the crude product, which was purified by column chromatrography over silica gel using ethyl acetate and hexane as eluent to give the carbinol amides 1a-q. 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 oC; 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);

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CNMR (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) calcd. for C18H16NO2 (M + H)+ 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 oC; 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), 3.683.73 (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) calcd. for C18H15ClNO2 (M + H)+ 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 oC; 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); CNMR (150 MHz, CDCl3) δ 19.7, 38.4, 81.4, 82.5, 88.5, 122.3, 122.4, 123.5, 123.6, 130.1,

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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) calcd. for C18H15BrNO2 (M + H)+ 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 oC; 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


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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) calcd. for C18H15FNO2 (M + H)+ 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 oC; 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) calcd. for C19H18NO2 (M + H)+ 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 oC; 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);

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CNMR (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) calcd. for C19H18NO2 (M + H)+ 292.1332, found 292.1337. 3-Hydroxy-2-(4-(4-methoxyphenyl)but-3-yn-1-yl)isoindolin-1-one (1g): Brown solid; Rf (hexane/EtOAc 1:1) 0.5; mp 150-152 oC; 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), 3.703.77 (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); CNMR (150 MHz, CDCl3) δ 19.8, 38.9, 55.5, 82.2, 82.6, 85.8, 114.1, 115.5, 123.5, 123.6,

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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) calcd. for C19H18NO3 (M + H)+ 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 oC; 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);

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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) calcd. for C12H12NO2 (M + H)+ 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 oC; 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);

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CNMR (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) calcd. for C14H16NO2 (M + H)+ 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 oC; 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); CNMR (150 MHz, CDCl3) δ 17.5, 27.4, 38.9, 81.5, 82.2, 89.2, 123.3, 123.5, 123.8, 127.8,

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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. HRMS (ESI) calcd. for C19H18NO2 (M + H)+ 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 oC; 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);

13

CNMR (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) calcd. for C19H17BrNO2 (M + H)+ 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 oC; 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) calcd. for C20H20NO2 (M + H)+ 306.1489, found 306.1486. 3-Hydroxy-2-(5-(4-methoxyphenyl)pent-4-yn-1-yl)isoindolin-1-one (1m): Pale yellow solid; Rf (hexane/EtOAc 1:1) 0.57; mp 123-125 oC; 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);


13

CNMR (150 MHz, CDCl3) δ


Page 14 of 27

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) calcd. for C20H20NO3 (M + H)+ 322.1438, found 322.1439. 3-Hydroxy-2-(5-(3-methoxyphenyl)pent-4-yn-1-yl)isoindolin-1-one (1n): Pale yellow solid; Rf (hexane/EtOAc 1:1) 0.56; mp 120-122 oC; 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), 7.467.54 (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) calcd. for C20H20NO3 (M + H)+ 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 oC; 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);

13

CNMR (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) calcd. for C19H17N2O4 (M + H)+ 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


Page 15 of 27 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 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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) calcd. for C17H16NO2S (M + H)+ 298.0896, found 298.0899. 3-(1-Hydroxy-3-oxo-2,3-dihydro-1H-inden-2-yl)propanenitrile (1q): Colourless 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) calcd. for C11H11N2O2 (M + H)+ 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 and 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-q. (1S*,9bS*)-1-Benzoyl-2,3-dihydro-1H-pyrrolo[2,1-a]isoindol-5(9bH)-one (2a):



Page 16 of 27

Colorless solid. Rf (hexane/EtOAc 1:1) 0.53; mp 109-111 oC; 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);

CNMR (150 MHz, CDCl3) δ 35.4, 41.9, 50.6, 66.0, 123.5, 124.2, 128.7, 129.0, 129.2,

13

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) calcd. for C18H16NO2 (M + H)+ 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 oC; 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) calcd. for C18H15ClNO2 (M + H)+ 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 oC; 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);

13

CNMR (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) calcd. for C18H15BrNO2 (M + H)+ 356.0281, found 356.0268 (79Br). (1S*,9bS*)-1-(4-Fluorobenzoyl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindol-5(9bH)-one (2d):


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Colorless solid; Rf (hexane/EtOAc 1:1) 0.57; mp 139-141 oC; 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);

13

CNMR (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;

19

F NMR (376 MHz,

CDCl3/C6F6) δ 58.5; IR (KBr, neat) 2931, 2889, 1697, 1677, 1016, 752 cm−1. HRMS (ESI) calcd. for C18H15FNO2 (M + H)+ 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 oC; yield 163 mg, 80%; 1H NMR (600 MHz, CDCl3) δ 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), 7.357.37 (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) calcd. for C19H18NO2 (M + H)+ 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 oC; 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) calcd. for C19H18NO2 (M + H)+ 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 oC; 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); CNMR (150 MHz, CDCl3) δ 35.4, 41.9, 50.2, 55.8, 66.2, 114.3, 123.5, 124.2, 129.0, 129.4,

13

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) calcd. for C19H18NO3 (M + H)+ 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 oC; 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) calcd. for C19H18NO2 (M + H)+ 292.1332, found 292.1333. (1S*,10bS*)-1-(4-Bromobenzoyl)-1,3,4,10b-tetrahydropyrido[2,1-a]isoindol-6(2H)-one (2k): Pale yellow solid; Rf (hexane/EtOAc 7:3) 0.52; mp 217-220 oC; 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); 13CNMR (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,


Page 18 of 27

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134.0, 135.5, 143.3, 167.0, 197.4; IR (KBr, neat) 2925, 2856, 1680, 1677, 1261, 1070, 689 cm−1. HRMS (ESI) calcd. for C19H17BrNO2 (M + H)+ 370.0437, found 370.0457 (79Br). (1S*,10bS*)-1-(4-Methylbenzoyl)-1,3,4,10b-tetrahydropyrido[2,1-a]isoindol-6(2H)-one (2l): Colorless solid; Rf (hexane/EtOAc 7:3) 0.51; mp 202-204 oC; 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) calcd. for C20H20NO2 (M + H)+ 306.1489, found 306.1487. (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 oC; 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);

13

CNMR (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) calcd. for C20H20NO3 (M + H)+ 322.1443, found 322.1442. (1S*,10bS*)-1-(3-Methoxybenzoyl)-1,3,4,10b-tetrahydropyrido[2,1-a]isoindol-6(2H)-one (2n):



Page 20 of 27

Pale yellow solid; Rf (hexane/EtOAc 7:3) 0.51; mp 151-153 oC; 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); CNMR (150 MHz, CDCl3) δ 20.1, 27.1, 39.3, 41.9, 55.6, 59.2, 112.3, 119.8, 120.4, 121.0,

13

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) calcd. for C20H20NO3 (M + H)+ 322.1443, found 322.1419. (1S*,10bS*)-1-(Thiophene-2-carbonyl)-1,3,4,10b-tetrahydropyrido[2,1-a]isoindol-6(2H)-one (2p): Colorless solid; Rf (hexane/EtOAc 7:3) 0.52; mp 183-185 oC; 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), 7.42 (d, J = 7.2 Hz, 1 H);

13

CNMR (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) calcd. for C17H16NO2S (M + H)+ 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 oC; 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);

13

CNMR (150 MHz, CDCl3) δ 31.1, 35.3, 66.8, 123.0, 124.3,


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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) calcd. for C11H11N2O2 (M + H)+ 203.0815, found 203.0806. Procedure for the reaction of 1f in presence of dry methanol: To a solution of 3-hydroxy2-(4-(o-tolyl)but-3-yn-1-yl)isoindolin-1-one

(1f)

(194

mg,

0.70

mmol)

in

dry

dichloromethane (3 mL), dry methanol (1 mL) and molecular sieves 4Å 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 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 and 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-1Hpyrrolo[2,1-a]isoindol-5(9bH)-one (4) as 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 (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) calcd. for C20H20NO2 (M + H)+ 306.1489, found 306.1516. General procedure for the treatment of 2b-c with KOH: To a stirred solution of 2b-2c (0.36 mmol) in dry methanol (3 mL) at 0 °C was added a solution of pottasium 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 presure. 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 and 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) calcd. for C18H15ClNO2 (M + H)+ 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 oC; 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); CNMR (150 MHz, CDCl3) δ 33.2, 42.2, 44.5, 66.8, 123.4, 124.1, 128.7, 128.9, 129.6,

13

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) calcd. for C18H15BrNO2 (M + H)+ 356.0281, found 356.0283.


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Acknowledgements MD gratefully acknowledges Indian Institute of Technology Guwahati for his fellowship. Authors are grateful to Council of Scientific and Industrial Research (CSIR), New Delhi, (Grant No. 02/0159/13/EMR-II) and CoE, MHRD, Govt of India for financial support. Authors are also thankful to Central Instrument Facility (CIF) of IIT Guwahati for NMR facilities. Supporting Information Available: compounds,

19

1

H,

13

C NMR and HRMS spectra of all new

F NMR spectra of 1d and 2d, nOe spectra of compound 4, and X-ray

crystallographic data of compound 2b. This material is available free of charge via the Internet at http://pubs.acs.org. References: 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, 3011-3021.



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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, 2450–2456 and references cited therein. 5) For 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-Hydroxy-5-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 N-Acyliminium 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 carbon-carbon bonds. Tetrahedron 1978, 34, 173-178. (c) Schoemaker, H. E.; Speckamp, W. N. Stereocontrolled synthesis of functionalized 1-azaspirans. Efficient synthesis of perhydrohistrionicotoxin. Tetrahedron 1980, 36, 951-958.


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8) (a) Brabandt, W. V.; Kimpe, N. D. Diastereoselective Ring Expansion of β-Lactams toward γ-Lactams via N-Acyliminium Intermediates. J. Org. Chem. 2005, 70, 3369-3374. (b) Brabandt, W. V.; Kimpe, N. D. Electrophile-Induced Ring Expansions of β-Lactams toward γ-Lactams. J. Org. Chem. 2005, 70, 8717-8722. (c) Dekeukeleire, S.; D’hooghe, M.; Kimpe, N. D. Diastereoselective Synthesis of Bicyclic γ-Lactams via Ring Expansion of Monocyclic β-Lactams. 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, 3011–3021. 10) Welch, W. M. Synthesis of 4,N-diaryl-2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3carboxamides. J. Org. Chem. 1982, 47, 886-888. 11) Kim, S. H.; Kim, H. G.; Choo, H.; Cha, J. H.; Pae, A. N.; Hun Yeong 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, 1062910641. (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 (±)-epi-indolizidine 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. The imidazo[2,1-a] isoindole system. A new skeletal basis for antiplasmodial compounds. Bioorg. Med. Chem. Lett. 2003, 13, 2769–2772. 19) Nesmeřák, K.; Pelouchová, H.; Všetečka, V.; Nčmec, I.; Gabriel, J. Antifungal effects of new heterocyclic compounds, 6H-pyrimido[2,1-a]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, 85928598.


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Table of Content

Substituted pyrroloisoindolones and pyridoisoindolones can effectively be synthesized from N-acyliminium ion intermediate derived from the triflic acid treatment of regioselectively reduced N-homopropargyl imides in good yields and high diastereoselectivity.


Stereoselective Synthesis of Pyrroloisoindolone and

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