HETEROCYCLES

Short Paper | Regular issue | Vol. 89, No. 5, 2014, pp. 1255-1259
Received, 8th March, 2014, Accepted, 26th March, 2014, Published online, 27th March, 2014.
DOI: 10.3987/COM-14-12974

■ Isoindolone Synthesis via Intramolecular Coupling of Benzylic C-H Bonds with Amide N-H Bonds

Ming Zhang,* Tianbao Chen, and Qinhua Liu

College of Chemistry, Jiangxi Normal University, 99 Ziyangdadao, Nanchang, Jiangxi, 330022 , China

Abstract

Four 7-methyl-2-(8-quinolinyl)-2,3-dihydro-1H-isoindol-1-ones were synthesized from 2,6-dimethyl-N-(8-quinolinyl)benzamides with exellent yields using Pd(OAc)2 as a catalyst, iodobenzene as an oxidant and AgOAc as an additive.

Construction of heterocyclic scaffolds via C-H functionalization is an important strategy in heterocycle synthesis.1,2 In 2011, Chen3 and Daugulis4 reported independently a picolinamide directed intramolecular coupling of a sp3 C-H bond with a N-H bond, affording effectively four-, five-, and six-membered heterocycles. In 2013, Chen5 reported palladium-catalyzed 8-aminoquinoline carboxamide directed intramolecular amination of C(sp3)–H and C(sp2)–H bonds, constructing pyrrolidones and indolinones. In the same time, we also found palladium-catalyzed 8-aminoquinoline carboxamide directed intramolecular amination of C(sp3)–H bonds, affording a series of isoindolones.6 Recently, copper-catalyzed methods were reported,7 in which 8-aminoquinoline carboxamides were also used as directing groups, forming β-lactams via C(sp3)-H functionalization.
We are interested in C(sp3)-H functionalization. We reported synthesis of four 7-methyl-2-(8-quinolinyl)-2,3-dihydro-1H-isoindol-1-ones from 2,6-dimethyl-N-(8-quinolinyl)-benzamides via intramolecular direct amination of benzylic C-H bonds (Scheme 1).6 Based on previous work (Scheme 1),6 we intent to effect arylation/oxidation of benzylic C-H bonds with 2,6-dimethyl-N-(8-quinolinyl)benzamides as substrates according to literature methods,8 we obtained the cyclization products via intramolecular C-N coupling rather than arylation products (Scheme 2). Given the isoindolone is an effective moiety in same medicines,9 the synthesis of their derivatives is important. In this paper, four 7-methyl-2-(8-quinolinyl)-2,3-dihydro-1H-isoindol-1-ones were synthesized with exellent yields (90-98%) using Pd(OAc)2 (10 mol%) as a catalyst, iodobenzene as an oxidant and AgOAc as an additive. The cyclization reactions did not occur in the absence of PhI or AgOAc. The amides 1e and 1f (Scheme 3) did not undergo the intramolecular cyclization under the reaction conditions as in Scheme 2. Under the reaction conditions, the amide 1e probably formed a five-membered cyclometalated aryl-Pd(II) complex from sp2 C-H activation on the benzene ring of the carboxylic acid, which probably is a stable intermediate. In this case, benzylic C-H activation did not occur.

A possible mechanism involves benzylic C-H activation of 1a-d to produce intermediate A (Scheme 4),6 then oxidative addition of A with PhI producing Pd(IV) species B, and reductive elimination to give the product and Pd(II) so completing the catalytic cycle (Scheme 4). A Pd(II)/Pd(0) catalytic cycle is also possible. Reductive elimination of intermediate A gives the product and Pd(0), oxidation of Pd(0) to Pd(II) is effected by the oxidative addition of Pd(0) with PhI, and completing the catalytic cycle.

In conclusion, we developed a new efficient method for synthesis of isoindolones, that is palladium-catalyzed 8-aminoquinoline carboxamide directed intramolecular amination of benzylic C-H bonds. It doesn’t need an acidic additive, and yields are exellent (90-98%).

EXPERIMENTAL
Amides 1a-f were prepared according to our previous methods.6 All reaction were performed under the atmosphere of nitrogen. 1H NMR and 13C NMR spectra were recorded on a Bruker Avance 400 spectrometer with TMS as the internal standard and CDCl3 as solvent. 19F NMR spectra were determined on a Bruker Avance 500 spectrometer. High-resolution mass spectra (HRMS) were obtained on a Waters Micromass GCT Premier spectrometer.

General procedure for synthesis of 7-methyl-2-(8-quinolinyl)-2,3-dihydro-1H-isoindol-1-ones (2a-d). To a tube were added an amide 1 (0.138 mmol), Pd(OAc)2 (10 mol%), PhI (8 equiv), AgOAc (2 equiv) and toluene (1 mL), then the reaction mixture was heated under an N2 atmosphere at 105 °C for 24 h. After cooling to rt, the mixture was concentrated in vacuo, and the residue was purified by flash column chromatography with petroleum ether–EtOAc (3:1 for 2a, and 4:1 for 2b-2d) as the eluent to afford the product. The product crystals were obtained by recrystallization with a mixed solvent of hexane and EtOAc.

5,7-Dimethyl-2-(8-quinolinyl)-2,3-dihydro-1H-isoindol-1-one (2a)6: pale yellow solid; mp 166-168 °C (lit.6, 166-168 °C). 1H NMR (400 MHz, CDCl3): δ = 2.44 (s, 3H, Me), 2.75 (s, 3 H, Me), 5.18 (s, 2 H, CH2), 7.07 (s, 1 H, ArH), 7.14 (s, 1 H, ArH), 7.41 - 7.44 (m, 1 H, ArH), 7.62 (t, J = 8 Hz, 1 H, ArH), 7.82 (app. d, Japp. = 8 Hz, 1 H, ArH), 7.91 (app. d, Japp. = 7.2 Hz, 1 H, ArH), 8.20-8.22 (m, 1 H, ArH), 8.87 - 8.89 (dd, J = 4, 1.6 Hz, 1 H, ArH). 13C NMR (100 MHz, CDCl3): δ = 17.38, 21.81, 53.09, 120.60, 121.44, 126.35, 127.12, 127.31, 128.90, 129.47, 130.96, 135.84, 136.42, 137.98, 141.87, 143.52, 144.51, 149.92, 169.73. HRMS (EI): m/z [M+] calcd for C19H16N2O: 288.1263; found: 288.1265.
7-Methyl-2-(8-quinolinyl)-2,3-dihydro-1H-isoindol-1-one (2b)6: colorless solid; mp 169-170 °C (lit.6, 169-170 °C). 1H NMR (400 MHz, CDCl3): δ = 2.79 (s, 3H, Me), 5.23 (s, 2 H, CH2), 7.24 (m, 1 H, ArH), 7.33 (app. d, Japp. = 7.6 Hz, 1 H, ArH), 7.41 - 7.49 (m, 2 H, ArH), 7.61-7.65 (m, 1 H, ArH), 7.82-7.84 (dd, J = 8.4, 1.2 Hz, 1 H, ArH), 7.91-7.93 (dd, J = 7.6, 1.2 Hz, 1 H, ArH), 8.20-8.23 (m, 1 H, ArH), 8.88-8.89 (dd, J = 4, 1.6 Hz, 1 H, ArH). 13C NMR (100 MHz, CDCl3): δ = 17.41, 53.21, 120.12, 121.35, 126.38, 127.44, 128.88, 129.49, 129.63, 129.86, 131.28, 135.79, 136.35, 138.35, 143.07, 144.50, 150.00, 169.63. HRMS (EI): m/z [M+] calcd for C18H14N2O: 274.1106; found: 274.1108.
5-Bromo-7-methyl-2-(8-quinolinyl)-2,3-dihydro-1H-isoindol-1-one (2c)6: pale yellow solid; mp 245-246 °C (lit.6, 245-246 °C). 1H NMR (400 MHz, CDCl3): δ = 2.75 (s, 3H, Me), 5.20 (s, 2 H, CH2), 7.40 - 7.43 (m, 2 H, ArH), 7.48 (s, 1 H, ArH), 7.60-7.64 (m, 1 H, ArH), 7.81-7.83 (dd, J = 8, 1.2 Hz, 1 H, ArH), 7.89-7.91 (dd, J1 = 7.6, 1.2 Hz, 1 H, ArH), 8.19-8.21 (m, 1 H, ArH), 8.86-8.87 (dd, J = 4, 1.6 Hz, 1 H, ArH). 13C NMR (100 MHz, CDCl3): δ = 17.18, 52.73, 121.45, 123.46, 125.85, 126.37, 127.62, 128.68, 128.84, 129.47, 132.94, 135.28, 136.39, 140.20, 144.32, 144.81, 150.08, 168.75. HRMS (EI): m/z [M+] calcd for C18H1379BrN2O: 352.0211; found: 352.0212.
5-Fluoro-7-methyl-2-(8-quinolinyl)-2,3-dihydro-1H-isoindol-1-one (2d)6: colorless solid; mp 178-179 °C (lit.6, 178-179 °C). 1H NMR (400 MHz, CDCl3): δ = 2.77(s, 3H, Me), 5.20 (s, 2 H, CH2), 6.94-7.01 (m, 2 H, ArH), 7.40-7.43 (m, 1 H, ArH), 7.61 (t, J = 8 Hz, 1 H, ArH), 7.81 (app. d, Japp. = 7.6 Hz, 1 H, ArH), 7.90 (app. d, Japp. = 7.6 Hz, 1 H, ArH), 8.18-8.21 (m, 1 H, ArH), 8.86-8.88 (m, 1 H, ArH). 13C NMR (100 MHz, CDCl3): δ = 17.43, 52.99 (d, 4JF-C = 2.8 Hz), 107.34 (d, 2JF-C = 23.7 Hz), 117.20 (d, 2JF-C = 22.3 Hz), 121.40, 125.77, 126.39, 127.49, 128.82, 129.49, 135.45, 136.39, 141.22 (d, 3JF-C = 9.3 Hz), 144.40, 145.49 (d, 3JF-C = 10.5 Hz), 150.03, 163.56, 167.36 (d, 1JF-C = 262 Hz). 19F NMR (470 MHz, CDCl3): δ = - 108.19. HRMS (EI): m/z [M+] calcd for C18H13FN2O: 292.1012; found: 292.1008.

ACKNOWLEDGEMENTS
This work was financially supported by the National Natural Science Foundation of China (No. 21262017) and a research project (GJJ10390) from Jiangxi Provincial department of Education, P. R. China.

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