HETEROCYCLES

Paper | Special issue | Vol. 79, No. 1, 2009, pp. 695-702
Received, 26th September, 2008, Accepted, 20th November, 2008, Published online, 21st November, 2008.
DOI: 10.3987/COM-08-S(D)36

■ Assembly of Substituted Homophthalimides via CuI-Catalyzed Coupling of 2-Bromobenzamides with β-Keto Ester

Hexiang Wang, Kun Gao, Yongwen Jiang, and Dawei Ma*

State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, 354 Finglin Road, Shanghai 200032, China

Abstract

CuI catalyzed coupling of 2-bromobenzamides and β-keto esters takes place at 90 °C in i-PrOH to afford substituted homophthalimides in good yields. This transformation undergoes a cascade coupling/intramolecular condensation process, which allows assembly of a wide range of substituted homophthalimides by varying 2-bromobenzamides and β-keto esters.

INTRODUCTION
Many biologically and pharmaceutically important molecules contain a homophthalimide moiety, which possess a wide range of biological activities from blocking auxin transport1 to inhibiting human rhinovirus 3C protease,2 cyclooxygenase,3 nitric oxide synthease,4 and cyclin-dependent kinase 4.5 Normally, these compounds were prepared via condensation of homophthalic anhydride with amines and subsequent introduction of functional groups.1-6

RESULTS AND DISCUSSION
In recent years we have witnessed great progress on development of mild conditions for copper-catalyzed cross-coupling reaction of aryl halides and activated methylene compounds.7 This advantage allowed us to establish some new methods for elaboration of heterocycles like polysubstituted indoles, benzofurans, 3-acyloxindoles and isoquinolines.8 As an extension of this work, in this paper, we explored the possibility of CuI-catalyzed coupling reaction of 2-bromobenzamides with β-keto esters. We envisaged that if the coupling reaction proceeds smoothly (Scheme 1), its products 3 may undergo an intramolecular condensation to afford substituted 1(2H)-isoquinolones 6 (via attacking the ketone group and subsequent dehydration, path A), or substituted homophthalimides 7 and their isomer 8 (via attacking the ester group, path B).

With this idea in mind, a coupling reaction of N-benzyl 2-bromobenzamide 1a with methyl acetoacetate 2a was conducted under our previous conditions (10 mol % CuI, 300 mol % K2CO3 in i-PrOH). We were pleased to find that after 22 h at 70 oC, homophthalimide 8a was isolated in 53% yield (entry 1, Table 1). Changing solvent to toluene, dioxane or THF gave worse results (entries 2-4). The yield was improved by switching base to K3PO4 (entry 5), and further improved by using Cs2CO3 (entry 6). After failed in increasing the yield by raising the reaction temperature (entry 7), we found that ideal yield could be obtained by increasing the amount of the base to 4 equiv (entry 8). The amount of methyl acetoacetate was also important as evident from that only 70% yield of 8a was obtained when 1.5 equiv of this ester was used (entry 9). The structure of 8a was established by X-ray analysis (Figure 1).

The optimized reaction conditions were further applied to other 2-bromobenzamides with β-keto esters and the results are summarized in Table 2. Generally, they all gave good yield of the corresponding homophthalimide as an enol form, which demonstrated that after coupling the intramolecular condensation took place exclusively between the ester and amide moieties (path B). In case of t-butyl substituted β-keto ester as a starting material, a homophthalimide was obtained in keto form (entry 2), while i-propyl substituted β-keto ester gave the corresponding homophthalimide as a mixture of enol and ketone forms in a ratio of about 10:1 (entry 1). These results indicated that the steric hindrance has great influence to the balance between ketone form and enol form products. The steric hindrance of the ketone part seems to have little effect to reaction yields because almost identical yields were observed for products 8a, 8b and 7c (entries 1 and 2). The olefin embodied and phenyl substituted β-keto esters also worked under these conditions, delivering homophthalimides 8d and 8e in good yields (entries 3 and 4). Additionally, variation of the N-substituents of homophthalimides 8f-k could be achieved by changing the N-substitutents of 2-bromobenzamides (entries 5-10). Furthermore, homophthalimides 8l-n were obtained in 52-92% yields (entries 11-13), indicating that functionalization at the aromatic ring of homophthalimides is possible using our method. Taken together, we concluded that the present method could elaborate substituted homophthalimides with considerable diversity.
When dimethyl malonate was used as a coupling partner, ester substituted homophthalimide 9 was obtained. In this case enol form product was observed as a major isomer while ketone form product 10 was determined as a minor isomer. The ratio for these two isomers was about 7.5:1.

In conclusion, we have developed a cascade coupling/intramolecular condensation process to assemble substituted homophthalimides from 2-bromobenzamides and β-keto esters. This method provides a convenient route for synthesizing these biologically important heterocycles with considerable diversity. Thus, it may find application in organic synthesis.

EXPERIMENTAL
General procedure for synthesis of substituted substituted homophthalimides (8). An oven-dried Schlenk tube was charged with CuI (19 mg, 0.1 mmol), Cs2CO3 (1.3 g, 4.0 mmol), and N-benzyl-o-bromobenzamide 1 (1 mmol). The tube was evacuated and backfilled with argon (3 times), and then β-keto ester 2 (2.0 mmol) and i-PrOH (3.0 mL) was added. The reaction mixture was stirred at 90 oC for 21-24 h. The cooled solution was poured into 1N HCl, extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5:1 to 1:1 petroleum ether/EtOAc) and the product was dried under vacuum for at least 1 h.
2-Benzyl-4-(1-hydroxyethylidene)-4H-isoquinoline-1,3-dione (8a) White solid, mp 124-125 oC; 1H NMR (300 MHz, CDCl3): δ 16.8 (s, 1H), 8.34 (d, Ј = 8.4 Hz, 1H), 7.58-7.60 (m, 2H), 7.46 (d, Ј = 6.9 Hz, 2H), 7.23-7.37 (m, 4H), 5.30 (s, 2H), 2.61(s, 3H); 13C NMR (100.0 MHz, CDCl3): δ 179.4, 166.5, 159.4, 133.1, 130.1, 129.4, 125.8, 125.1, 124.7 (2×C), 123.8 (2×C), 121.7, 120.4, 119.1, 96.3, 39.8, 21.6. EI-MS m/z 293 (M+); EI-HRMS calcd for C18H15NO3 (M +) 293.1052, found 293.1053.
2-Benzyl-4-(1-hydroxy-2-methylpropylidene)-4H-isoquinoline-1,3-dione (8b) White solid; mp 133-134 oC, 1H NMR (300 MHz, CDCl3): δ Enol form: 16.7 (s, 1H), 8.34 (d, Ј = 8.1 Hz, 1H), 7.47-7.58 (m, 4H), 7.23-7.36 (m, 4H), 5.31 (s, 2H), 3.51-3.59 (m, 1H), 1.37 (d, Ј = 6.9 Hz, 6H); Keto form: 8.27 (d, Ј = 8.1 Hz, 1H), 7.47-7.58 (m, 4H), 7.23-7.36 (m, 4H), 5.28 (s, 1H), 5.18-5.23 (m, 2H), 2.93-3.00 (m, 1H), 1.13 (d, Ј = 6.9 Hz, 3H), 1.03 (d, Ј = 6.9 Hz, 3H); 13C NMR (100.0 MHz, CDCl3): δ 190.0, 170.3, 163.2, 136.8, 133.6, 133.0, 129.3, 128.7 (2×C), 128.6, 128.3, 127.4, 125.3, 124.1, 123.0, 98.6, 43.4, 32.9, 19.9 (2×C). EI-MS m/z 321 (M+); EI-HRMS calcd for C20H19NO3 (M+) 321.1365, found 321.1367.
2-Benzyl-4-(pivaloyl)-4H-isquinoline-1,3-dione (7c) White solid; mp 116-117 oC, 1H NMR (300 MHz, CDCl3): δ 8.23 (dd, Ј = 7.8, 1.5 Hz, 1H), 7.44-7.52 (m, 2H), 7.36 (d, Ј = 8.4 Hz, 2H), 7.20-7.29 (m, 2H), 7.15 (d, Ј = 7.5 Hz, 1H), 5.62 (s, 1H), 5.14 (d, Ј = 13.8 Hz, 1H), 5.07 (d, Ј = 13.8 Hz, 1H), 1.27 (s, 9H); 13C NMR (100.0 MHz, CDCl3): δ 204.8, 167.6, 165.0, 136.6, 133.9, 133.3 (2×C), 129.5, 128.4, 128.3 (2×C), 128.2, 127.3, 126.9, 126.0, 56.2, 46.4, 43.8, 26.3 (3×C). EI-MS m/z 335 (M+); EI-HRMS calcd for C21H21NO3 (M+) 335.1521, found 335.1529.
2-Benzyl-4-(1-hydroxypent-4-enylidene)-4H-isoquinoline-1,3-dione (8d) White solid; mp 99-100 oC, 1H NMR (300 MHz, CDCl3): δ 16.9 (s, 1H), 8.34 (d, Ј = 8.1 Hz, 1H), 7.21-7.63 (m, 8H), 5.84-5.98 (m, 1H), 5.31 (s, 2H), 5.06-5.19 (m, 2H), 3.02 (t, Ј = 7.5 Hz, 2H), 2.55-2.63 (m, 2H); 13C NMR (100.0 MHz, CDCl3): δ 185.4, 170.2, 163.1, 136.8, 136.4, 133.5, 133.1, 129.5, 128.7 (2×C), 128.5, 128.4, 127.5, 125.4, 124.0, 122.8, 116.0, 99.9, 43.5, 36.0, 29.8. ESI-MS m/z 334.2 (M + Na)+; ESI-HRMS calcd for C21H19NO3 (M + Na)+ 356.12572, found 356.1256.
2-Benzyl-4-(hydroxyphenylmethylene)-4H-isoquinoline-1,3-dione (8e)9 Yellow solid; mp 105-106 oC, 1H NMR (300 MHz, CDCl3): δ 16.7 (s, 1H), 8.24 (dd, Ј = 7.8, 1.2 Hz, 1H), 7.42-7.56 (m, 7H), 7.10-7.35 (m, 5H), 6.81 (d, Ј = 7.5 Hz, 1H), 5.36 (s, 2H); 13C NMR (100.0 MHz, CDCl3): δ 180.5, 170.5, 163.3, 136.7, 136.1, 133.4, 131.9, 131.5, 129.0, 128.9, 128.8 (2×C), 128.7, 128.6 (2×C), 128.4 (2×C), 127.6, 125.6, 125.5, 122.9, 99.1, 43.6. ESI-MS 356.2 (M + H)+; ESI-HRMS calcd for C23H17NO3Na (M + Na)+ 378.11007, found 378.1100.
2-Allyl-4-(1-hydroxyethylidene)-4H-isoquinoline-1,3-dione (8f) White solid; mp 87-88 oC, 1H NMR (300 MHz, CDCl3): δ 16.8 (s, 1H), 8.34 (d, Ј = 8.1 Hz, 1H), 7.60-7.63 (m, 2H), 7.33-7.38 (m, 1H), 5.88-6.01 (m, 1H), 5.26 (dd, Ј = 17.4, 1.5 Hz, 1H), 5.20 (dd, Ј = 10.5, 1.5 Hz, 1H), 4.73 (d, Ј = 5.7 Hz, 2H), 2.64 (s, 3H); 13C NMR (100.0 MHz, CDCl3): δ 183.0, 169.9, 162.8, 133.8, 133.1, 131.8, 129.4, 125.3, 124.0, 122.7, 117.6, 99.9, 42.3, 25.2. ESI-MS m/z 244.0 (M + H)+; ESI-HRMS calcd for C14H14NO3 (M + H)+ 244.09682, found 244.0974.
2-Butyl-4-(1-hydroxyethylidene)-4H-isoquinoline-1,3-dione (8g)10 White solid; mp 62-63 oC, 1H NMR (300 MHz, CDCl3): δ 17.0 (s, 1H), 8.32 (d, Ј = 7.8 Hz, 1H), 7.59-7.60 (m, 2H), 7.32-7.37 (m, 1H), 4.10 (t, Ј = 7.5 Hz, 2H), 2.63 (s, 3H), 1.61-1.74 (m, 2H), 1.37-1.45 (m, 2H), 0.96 (t, Ј = 7.2 Hz, 3H); 13C NMR (100.0 MHz, CDCl3): δ 183.0, 170.2, 163.0, 133.7, 132.9, 129.2, 125.2, 123.9, 122.8, 99.8, 40.2, 29.9, 25.3, 20.3, 13.7. ESI-MS m/z 260.2 (M+H)+; ESI-HRMS calcd for C15H18NO3 (M + H)+ 260.12812, found 260.1285.
4-(1-Hydroxyethylidene)-2-phenyl-4H-isoquinoline-1,3-dione (8h) White solid; mp 168-169 oC, 1H NMR (300 MHz, CDCl3): δ 16.5 (s, 1H), 8.36 (d, Ј = 7.8 Hz, 1H), 7.68 (d, Ј = 4.2 Hz, 2H), 7.37-7.57 (m, 4H), 7.25-7.27 (m, 2H), 2.69 (s, 3H); 13C NMR (100.0 MHz, CDCl3): δ 183.6, 170.7, 163.5, 135.1, 134.3, 133.7, 129.9, 129.7 (2×C), 129.1, 128.7 (2×C), 125.8, 124.6, 123.4, 100.4, 25.5. EI-MS m/z 279 (M+); EI-HRMS calcd for C19H17NO4 (M+) 323.1158, found 323.1146.
2-[3-(tert-Butyldimethylsilanyloxy)propyl]-4-(1-hydroxyethylidene)-4H-isoquinoline-1,3-dione (8i) Colorless oil;. 1H NMR (300 MHZ, CDCl3): δ 17.0 (s, 1H), 8.31 (d, Ј = 7.8 Hz, 1H), 7.59-7.60 (m, 2H), 7.31-7.37 (m, 1H), 4.19 (t, Ј = 7.5 Hz, 2H), 3.73 (t, Ј = 6.3 Hz, 2H), 2.62 (s, 3H), 1.86-1.95 (m, 2H), 0.87 (s, 9H), 0.03 (s, 6H); 13C NMR (100.0 MHz, CDCl3): δ 183.0, 170.2, 163.0, 133.7, 132.9, 129.3, 125.2, 124.0, 122.8, 99.9, 61.2, 38.1, 31.0, 25.8 (3×C), 25.3, 18.2, -5.4 (2×C). EI-MS m/z 375 (M+); EI-HRMS calcd for C20H29NO4Si (M+) 375.1866, found 375.1862
4-(1-Hydroxyethylidene)-2-(4-methoxybenzyl)-4H-isoquinoline-1,3-dione (8j) White solid; mp 140-141 oC, 1H NMR (300 MHz, CDCl3): δ 16.9 (s, 1H), 8.34 (d, Ј = 7.8 Hz, 1H), 7.59 (d, Ј = 2.4 Hz, 2H), 7.46 (d, Ј = 8.4 Hz, 2H), 7.29-7.36 (m, 1H), 6.82 (d, Ј = 8.4 Hz, 2H), 5.24 (s, 2H), 3.76 (s, 3H), 2.62 (s, 3H); 13C NMR (100.0 MHz, CDCl3): δ 183.0, 170.1, 163.1, 159.0, 133.7, 133.1, 130.5 (2×C), 129.4, 129.1, 125.3, 124.0, 122.8, 113.7 (2×C), 100.0, 55.2, 42.9, 25.3. EI-MS m/z 323 (M+); EI-HRMS calcd for C19H17NO4 (M+) 323.1158, found 323.1154.
2-(4-Chlorobenzyl)-4-(1-hydroxyethylidene)-4H-isoquinoline-1,3-dione (8k) White solid; mp 152-153 oC, 1H NMR (300 MHz, CDCl3): δ 16.7 (s, 1H), 8.33 (d, Ј = 8.1 Hz, 1H), 7.57-7.61 (m, 2H), 7.42 (d, Ј = 8.4 Hz, 2H), 7.31-7.37 (m, 1H), 7.25 (d, Ј = 8.4 Hz, 2H), 5.25 (s, 2H), 2.62 (s, 3H); 13C NMR (100.0 MHz, CDCl3): δ 183.2, 170.0, 163.1, 135.3, 133.7, 133.4, 133.2 (2×C), 130.4, 129.5 (2×C), 128.5, 125.4, 124.1, 122.6, 100.0, 42.8, 25.2. EI-MS m/z 327 (M+); EI-HRMS calcd for C18H14NO3Cl (M+) 327.0662, found 327.0670.
2-Benzyl-4-(1-hydroxyethylidene)-7-methoxy-4H-isoquinoline-1,3-dione (8l) White solid; mp 149-150 oC, 1H NMR (300 MHz, CDCl3): δ 16.6 (s, 1H), 7.81 (d, Ј = 3.0 Hz, 1H), 7.53 (d, Ј = 9.3 Hz, 1H), 7.47 (d, Ј = 6.6 Hz, 2H), 7.18-7.33 (m, 4H), 5.31 (s, 2H), 3.88 (s, 3H), 2.59 (s, 3H); 13C NMR (100.0 MHz, CDCl3): δ 181.5, 169.9, 163.0, 157.2, 136.8, 128.7 (2×C), 128.4 (2×C), 127.5, 127.0, 125.6, 123.9, 122.1, 110.7, 99.9, 55.6, 43.6, 25.1. EI-MS m/z 323 (M+); EI-HRMS calcd for C19H17NO4 (M +) 323.1158, found 323.1146.
2-Benzyl-7-chloro-4-(1-hydroxyethylidene)-4H-isoquinoline-1,3-dione (8m) White solid; mp 142-143 oC, 1H NMR (300 MHz, CDCl3): δ 16.8 (s, 1H), 8.31 (s, 1H), 7.53 (d, Ј = 1.2 Hz, 2H), 7.46 (d, Ј = 6.9 Hz, 2H), 7.25-7.33 (m, 3H), 5.30 (s, 2H), 2.61(s, 3H); 13C NMR (100.0 MHz, CDCl3): δ 183.5, 169.9, 162.1, 136.6, 133.2, 132.2, 131.4, 129.0, 128.9 (2×C), 128.5 (2×C), 127.7, 125.5, 124.1, 99.5, 43.7, 25.4. EI-MS m/z 327 (M+); EI-HRMS calcd for C18H14NO3Cl (M+) 327.0662, found 327.0660
2-Benzyl-6-chloro-4-(1-hydroxyethylidene)-4H-isoquinoline-1,3-dione (8n) White solid; mp 173-174 oC, 1H NMR (300 MHz, CDCl3): δ 17.0 (s, 1H), 8.28 (d, Ј = 8.7 Hz, 1H), 7.58 (d, Ј = 1.5 Hz, 1H), 7.46 (d, Ј = 7.2 Hz, 2H), 7.26-7.33 (m, 4H), 5.29 (s, 2H), 2.64(s, 3H); 13C NMR (100.0 MHz, CDCl3): δ 184.2, 170.1, 162.4, 139.8, 136.6, 135.2, 131.1, 128.8, 128.4 (2×C), 127.6 (2×C), 125.7, 123.8, 121.0, 99.3, 43.6, 25.4. EI-MS m/z 327 (M+); EI-HRMS calcd for C18H14NO3Cl (M+) 327.0662, found 327.0660.
2-Benzyl-3-hydroxy-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid methyl ester (9) White solid; mp 138-139 oC, 1H NMR (300 MHz, CDCl3): δ Enol form: 15.89 (s, 1H), 8.40 (m, 2H), 7.61 (t, Ј = 7.2 Hz, 1H), 7.46 (d, Ј = 7.5 Hz, 2H), 7.25-7.31 (m, 4H), 5.41 (s, 2H), 4.05 (s, 3H); Keto form: 8.23 (d, Ј = 7.5 Hz, 2H), 7.61 (t, Ј = 7.2 Hz, 1H), 7.46 (d, Ј = 7.5 Hz, 2H), 7.25-7.31 (m, 4H), 5.26 (d, J = 14.1 Hz, 1H), 5.15 (d, J = 14.1 Hz, 1H), 4.93 (s, 1H), 3.67 (s, 3H); 13C NMR (100.0 MHz, CDCl3): δ 174.0, 164.1, 162.0, 136.4, 133.6, 128.7, 128.6, 128.5, 128.4 (2×C), 128.37, 127.6, 124.3, 124.1, 120.9, 84.7, 52.8, 44.7. EI-MS m/z 309 (M+); EI-HRMS calcd for C18H15NO4 (M+) 309.1001, found 309.1003.

ACKNOWLEDGEMENTS
The authors are grateful to the Chinese Academy of Sciences, National Natural Science Foundation of China (grant 20621062 & 20572119) for their financial support.

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