一个高效的合成异香豆素类化合物通过崔催化串联反应过程

Science in China Series B: Chemistry© 2009 SCIENCE IN CHINA PRESSSpringer An efficient synthesis of isocoumarins via a CuI catalyzed cascade reaction processWANG LeiLei 1, ZHANG XiaoJing 1, JIANG YongWen 2† & MA DaWei 2†1 Shenyang Pharmaceutical University, Shenyang 110016, China;2State Key Laboratory of Bioorganic Chemistry and Natural Products, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China3-Alkyl isocoumarins are provided by CuI/amino acid-catalyzed Sonogashira coupling reaction of o -bromo benzoic acids and terminal alkynes and the subsequent additive cyclization. This cascade process allows synthesis of diverse isocoumarins by varying both coupling partners bearing a wide range of functional groups.coupling, cascade reaction, copper iodide, isocoumarins1 IntroductionIsocoumarins exist in many naturally occurring lactoneswith various biological activities, such as antifungal,antibacterial, and anti-diabetic effects [1―7]. For example,compound 185322 is a novel inhibitor of microtubule assembly that induces mitotic phase arrest and apoptosis of human multiple myeloma cells [8], and bacilosarcin Bisolated from the marine-derived bacterium Bacillussubtilis shows growth inhibition against barnyard mil-let (Figure 1)[9].Figure 1Early studies have indicated that simple isocoumarins could be synthesized from 2-bromobenzoate and ethyl- ene via a Pd-catalyzed Heck reaction and subsequent transformation [10]. A Pd-catalyzed domino Sonogashira coupling/cyclization process of o -halobenzoic acid and1-alkynes was then developed for the same purpose [11―17].In this process, selectivity for 5-exo and 6-endo cycliza-tion is a problem, which relies on Pd catalyst [11―15], sub-strates [16] and solvent [17].On the basis of CuI/amino acid-promoted Ullmann type coupling reactions, our group has developed a se-ries of methods for the assembly of heterocycles under mild reaction conditions [18―21; 22―30]. For example, 2-sub- stituted indoles could be elaborated via a CuI/L-prolinecatalyzed domino Sonogashira coupling/cyclizationprocess [26,31]. Stimulated by this result, we investigated the coupling of 2-halobenzoic acid with terminal alkynes under the catalysis of CuI, and found that 3-alkyl sub- stituted isocoumarins could be obtained regioselectively. Both iodides and bromides are available for this domino process, thereby providing an inexpensive and practical approach for the assembly of isocoumarins. 2 Experiments2.1 ExperimentalAll solvents were purified and dried prior to use. 1HReceived July 20, 2009; accepted July 23, 2009 doi: 10.1007/s11426-009-0197-6 †Corresponding author (email: madw@ )Supported by the National Natural Science Foundation of China (Grant Nos. 20621062 & 20872156),Sci China Ser B-Chem | Oct. 2009 | vol. 52 | no. 10 | 1616-1621NMR spectra were recorded at Bruker Avance 300 MHz, and 13C NMR spectra were recorded at Bruker Avance 400 MHz, and assigned in parts per million (δ). Low-resolution mass spectra were recorded on a GILENT5973 instrument (EI) and a LCMS-2010EV instrument (ESI). High-resolution mass spectra were recorded on an IonSpec 4.7 Tesla FTMS instrument. Silica gel plate GF254 was used for thin layer chroma-tography (TLC) and silica gel H or 300―400 meshes were used for flash column chromatography.2.2 General procedure of synthesisAn oven-dried Schlenk tube was charged with CuI (0.20 mmol), trans-4-hydroxy-L-proline (26 mg, 0.20 mmol) and K2CO3 (276 mg, 2 mmol), and 2-bromobenzoic acid1 (1.0 mmol). The tube was evacuated and backfilled with argon (3 times), and then alkyne2 (1.5 mmol) and DMSO (2.0 mL) were added. The reaction mixture was stirred at 70℃ until the 2-bromobenzoic acid 1 disap-peared (monitored by TLC). After cooling, 30 mL ethyl acetate was added. The organic layer was separated, washed with water and brine, and dried over Na2SO4. After removal of the solvent in vacuo, the residue was purified by silica gel chromatography to give the desired isocoumarin 3.(1) 3-Pentyl-1H-isochromen-1-one (3a). 1H NMR (300 MHz, CDCl3) δ 8.24 (d, J=8.1 Hz, 1 H), 7.66 (t, J=7.5 Hz, 1 H), 7.43 (t, J=8.1 Hz, 1 H), 7.35 (d, J= 7.8 Hz, 1 H), 6.25 (s, 1 H, CH=C), 2.51 (t, J=7.8 Hz,2 H, CH2), 1.73―1.68 (m, 2 H, CH2), 1.37―1.34 (m, 4 H, 2CH2), 0.90 (t, J=6.3 Hz, 3 H, CH3). EI-MS m/z 216 (M+).(2) 3-(2-Hydroxypropan-2-yl)-1H-isochromen-1-one (3b). 1H NMR (300 MHz, CDCl3) δ 8.25 (d, J=8.1 Hz, 1 H), 7.69 (t, J=7.2 Hz, 1 H), 7.47 (t, J=7.8 Hz, 1 H), 7.41 (d,J=7.8 Hz, 1 H), 6.64 (s, 1 H, CH=C), 2.82 (bs, 1 H, OH), 1.60 (s, 6 H, 2CH3). EI-MS m/z 204 (M+).(3) Ethyl-5-(1-oxo-1H-isochromen-3-yl)pentanoate (3c). 1H NMR (300 MHz, CDCl3) δ 8.24 (d, J=7.8 Hz, 1 H), 7.67 (t, J=7.5 Hz, 1 H), 7.45 (t, J=8.1 Hz, 1 H), 7.35 (d,J=7.5 Hz, 1 H), 6.28 (s, 1 H, CH=C), 4.13 (q, J=7.2 Hz,2 H), 2.55 (t, J=6.9 Hz, 2 H, CH2), 2.35 (t, J=6.6 Hz,2 H, CH2), 1.74―1.72 (m, 4 H, 2CH2), 1.25 (t, J=7.2 Hz,3 H, CH3). EI-MS m/z 274 (M+).(4) 3-Butyl-1H-isochromen-1-one (3d).1H NMR (300 MHz, CDCl3) δ 8.23 (d, J=7.8 Hz, 1 H), 7.66 (t, J=7.8 Hz, 1 H), 7.43 (t, J=8.1 Hz, 1 H), 7.34 (d, J= 7.8 Hz, 1 H), 6.25 (s, 1 H, CH=C), 2.52 (t, J=7.5 Hz, 2 H, CH2), 1.74―1.64 (m, 2 H, CH2), 1.46―1.34 (m, 2 H, CH2), 0.94 (t, J=7.2 Hz, 3 H, CH3). EI-MS m/z 202 (M+).(5) 3-(Hydroxymethyl)-1H-isochromen-1-one (3e). 1H NMR (300 MHz, CDCl3) δ 8.28 (d, J=8.1 Hz, 1 H), 7.72 (t, J=7.2 Hz, 1 H), 7.51 (t, J=7.8 Hz, 1 H), 7.43 (d, J=7.8 Hz, 1 H), 6.56 (s, 1 H, CH=C), 4.50 (s, 2 H, CH2), 1.83 (bs, 1 H, OH). EI-MS m/z 176 (M+).(6) 3-(Benzyloxymethyl)-1H-isochromen-1-one (3f). l H NMR (300 MHz, CDC13) δ 8.24 (d, J=8.1 Hz, 1 H), 7.67 (t, J=7.2 Hz, l H), 7.46 (t, J=7.5 Hz, l H ), 7.39―7.29 (m, 6 H), 6.55 (s, l H, CH=C), 4.65 (s, 2 H, OCH2), 4.34 (s, 2 H, OCH2). 13C NMR (100 MHz, CDCl3) δ162.2, 153.6, 137.2, 136.7, 134.8, 129.6, 128.5 (2C), 128.2, 127.9, 127.8 (2C), 125.6, 120.6, 103.9, 73.1, 67.9. EI-MS m/z 266 (M+).(7) Methyl-(1-oxo-1H-isochromen-3-yl)methylc-arbamate (3g). l H NMR (300 MHz, CDC13) δ 8.23 (d, J=7.8 Hz, 1 H), 7.69 (t, J=7.5 Hz, l H), 7.48 (t, J=7.8 Hz, l H), 7.39 (d, J=7.5 Hz, 1 H), 6.49 (s, l H, CH=C), 5.53 (s, 1 H, NH), 4.21 (d, J=6.3 Hz, 2 H, CH2), 3.70 (s, 3 H, COOCH3). 13C NMR (100 MHz, CDCl3) δ 162.2, 156.8, 153.1, 136.6, 134.8, 129.4, 128.2, 125.5, 120.2, 103.5, 52.3, 42.3. EI-MS m/z 233 (M+).(8) 3-(1-Hydroxypropyl)-1H-isochromen-1-one (3h). l H NMR (300 MHz, CDC13) δ 8.22 (d, J=7.8 Hz, 1 H), 7.68 (t, J=7.8 Hz, l H), 7.47 (t, J=7.8 Hz, l H), 7.39 (d, J=7.5 Hz, 1 H), 6.56 (s, l H, CH=C), 4.41 (t, J=7.2 Hz, l H), 2.81 (bs, 1 H, OH), 2.04―1.77 (m, 2 H, CH2), 1.00 (t, 3 H, J=7.5 Hz, CH3). EI-MS m/z 204 (M+).(9) 3-(1-Hydroxyhexyl)-1H-isochromen-1-one (3i). l H NMR (300 MHz, CDC13) δ 8.25 (d, J=8.1 Hz, 1 H), 7.70 (t, J=7.8 Hz, l H), 7.49 (t, J=7.8 Hz, l H), 7.41 (d, J=8.1 Hz, 1 H), 6.55 (s, l H, CH=C),4.48―4.44 (m, l H), 2.20 (bs, 1 H, OH), 1.96―1.72 (m, 2 H, CH2), 1.49―1.25 (m, 6 H, 3CH2), 0.88 (t, 3H, J.=6.6 Hz, CH3). 13C NMR (100 MHz, CDCl3) δ 162.5, 158.4, 136.9, 134.8, 129.4, 128.0, 125.7, 120.3, 102.0, 70.9, 34.9, 31.4, 24.9, 22.4, 13.9. EI-MS m/z 246 (M+).(10) 3-Benzyl-1H-isochromen-1-one (3j). l H NMR (300 MHz, CDC13) δ 8.24 (d, J=7.8 Hz, 1 H) ,7.62 (t, J=7.8 Hz, l H), 7.44 (t, J=7.8 Hz, l H), 7.38―7.29 (m,WANG LeiLei et al. Sci China Ser B-Chem | Oct. 2009 | vol. 52 | no. 10 | 1616-162116176 H), 6.16 (s, l H, CH=C), 3.84 (s, 2 H, CH2). 13C NMR (100 MHz, CDCl3) δ 162.7, 156.9, 137.2, 135.6, 134.6, 129.4, 129.2, 128.7, 127.7, 127.1, 125.2, 120.0, 103.8, 39.7. EI-MS m/z 236 (M+).(11) 3-Butyl-7-methoxy-1H-isochromen-1-one (3l). 1H NMR (300 MHz, CDCl3) δ 7.66 (s, 1 H), 7.28-7.27 (m, 2 H), 6.22 (s, 1 H, CH=C), 3.89 (s, 3 H, CH3O), 2.51 (t,J=7.5 Hz, 2 H, CH2), 1.73―1.63 (m, 2 H, CH2), 1.46―1.33 (m, 2 H, CH2), 0.94 (t, J=7.2 Hz, 3 H, CH3). EI-MS m/z 232 (M+).(12) 3-(2-Hydroxypropan-2-yl)-7-methoxy-1H-isochromen-1-one (3m). 1H NMR (300 MHz, CDCl3) δ 7.68 (d, J= 2.7 Hz, 1 H), 7.37 (d, J=8.7 Hz, 1 H), 7.30 (dd, J=2.7, 8.4 Hz, 1 H), 6.58 (s, 1 H, CH=C), 3.90 (s, 3 H, CH3O), 2.25 (bs, 1 H, OH), 1.60 (s, 6 H, 2CH3). EI-MS m/z 234 (M+).(13) Methy-5-(7-methoxy-1-oxo-1H-isochromen-3-yl)pen- tanoate (3n). 1H NMR (300 MHz, CDCl3) δ 7.66 (s, 1 H), 7.28―7.26 (m, 2 H), 6.24 (s, 1 H, CH=C), 4.13 (q, J= 7.2 Hz, 2 H), 3.89 (s, 3 H, CH3O), 2.54 (t, J=6.6 Hz, 2 H, CH2), 2.34 (t, J=6.2 Hz, 2 H, CH2), 1.74―1.71 (m, 4 H,2CH2), 1.25 (t, J=7.2 Hz, 3 H, CH3). 13C NMR (100 MHz, CDCl3) δ 173.3, 163.1, 159.0, 155.3, 131.1, 126.6, 124.4, 121.1, 109.8, 102.7, 60.2, 55.6, 33.9, 32.9, 26.3, 24.2, 14.2. EI-MS m/z 304 (M+).(14) N-(3-butyl-1-oxo-1H-isochromen-7-yl)acetamide (3o). 1H NMR (300 MHz, CD3OD) δ 8.39 (d, J=1.8 Hz, 1 H), 7.92 (dd, J=1.8, 8.4 Hz, 1 H), 7.44 (d, J=8.7 Hz, 1 H), 6.43 (s, 1 H, CH=C), 2.54 (t, J=7.2 Hz, 2 H, CH2), 2.15 (s, 3 H, CH3CO), 1.73―1.62 (m, 2 H, CH2), 1.47―1.35 (m, 2 H, CH2), 0.96 (t, J=7.2 Hz, 3 H, CH3). EI-MS m/z 259 (M+).(15) N-(3-(2-hydroxypropan-2-yl)-1-oxo-1H-isochromen-7-yl)acetamide (3p). 1H NMR (300 MHz, (CD3)2SO) δ10.31 (s, 1 H, NH), 8.47 (s, 1 H), 7.90 (dd, J=1.2, 8.1 Hz,1 H), 7.61 (d, J=8.1 Hz, 1 H), 6.73 (s, 1 H, CH=C), 5.47 (bs, 1 H, OH), 2.08 (s, 3 H, COCH3), 1.41 (s, 6 H, 2CH3). 13C NMR (100 MHz, CDCl3) δ 169.0, 162.1, 161.9, 139.4, 132.6, 127.2, 126.6, 120.0, 117.4, 99.5, 69.7, 28.6 (2C), 24.4. EI-MS m/z 261 (M+).(16) 3-Butyl-6-methyl-1H-isochromen-1-one (3q). 1H NMR (300 MHz, CDCl3) δ 8.09 (d, J=8.1 Hz, 1 H), 7.22 (d, J=8.4 Hz, 1 H), 7.11 (s, 1 H), 6.16 (s, 1 H, CH=C), 2.48 (t, J=7.2 Hz, 2 H, CH2), 2.42 (s, 3 H, CH3), 1.71―1.61 (m, 2 H, CH2), 1.43―1.31 (m, 2 H, CH2), 0.92 (t, J=7.2 Hz, 3 H, CH3). EI-MS m/z 216 (M+).(17) 6-Chloro-3-(2-hydroxypropan-2-yl)-1H-isochromen- 1-one (3r). 1H NMR (300 MHz, CDCl3) δ 8.23 (d, J= 1.5 Hz,1 H), 7.65 (dd, J=2.1, 8.4 Hz, 1 H), 7.38 (d, J= 8.1 Hz, 1 H), 6.63 (s, 1 H, CH=C), 2.23 (bs, 1 H, OH), 1.60 (s, 6 H, 2CH3). EI-MS m/z 238 (M+).(18) 3-butyl-6-chloro-1H-isochromen-1-one (3s). 1H NMR (300 MHz, CDCl3) δ 8.22 (d, J=1.2 Hz, 1 H), 7.61 (dd, J=2.4, 8.4 Hz, 1 H), 7.31 (d, J=8.4 Hz, 1 H), 6.24 (s, 1 H, CH=C), 2.53 (t, J=7.5 Hz, 2 H, CH2), 1.74―1.64 (m, 2 H, CH2), 1.46―1.34 (m, 2 H, CH2), 0.95 (t, J=7.2 Hz, 3 H, CH3). EI-MS m/z 236 (M+). (19) 3-(2-Hydroxypropan-2-yl)-7-nitro-1H-isochromen- 1-one (3t). 1H NMR (300 MHz, CDCl3) δ 9.18 (d, J= 1.5 Hz, 1 H), 8.51 (dd, J=2.4, 9.0 Hz, 1 H), 7.60 (d, J= 8.4 Hz, 1 H), 6.79 (s, 1 H, CH=C), 2.14 (bs, 1 H, OH), 1.62 (s, 6 H, 2CH3). EI-MS m/z 249 (M+).(20)7,8-Dimethoxy-3-pentyl-1H-isochromen-1-one (3u). 1H NMR (300 MHz, CDCl3) δ 7.24 (d, J=8.4 Hz, 1 H), 7.00 (d, J=8.4 Hz, 1 H), 6.06 (s, 1 H, CH=C), 3.90 (s, 3 H, CH3O), 3.86 (s, 3 H, CH3O), 2.39 (t, J=7.5 Hz, 2 H, CH2), 1.64―1.59 (m, 2 H, CH2), 1.28―1.27 (m, 4 H, 2CH2), 0.84 (t, J=6.3 Hz, 3 H, CH3). 13C NMR (100 MHz, CDCl3) δ 159.6, 156.0, 152.0, 150.7, 132.2, 120.7, 120.5, 114.5, 102.2, 61.4, 56.5, 33.0, 31.1, 26.4, 22.3, 13.9. EI-MS m/z 276 (M+).(21) 3-Hexylidene-6,7-dimethoxy-3H-isobenzofuran- 1-one (4u). 1H NMR (300 MHz, CDCl3) δ 7.28 (d, J= 8.4 Hz, 1 H), 7.23 (d, J=8.1 Hz, 1 H), 5.46 (t, J=7.8 Hz,1 H), 4.12 (s,3 H, CH3O), 3.93 (s, 3 H, CH3O), 2.38―2.45 (m, 2 H, CH2), 1.47―1.51 (m, 2 H, CH2), 1.33―1.36 (m, 4 H, 2CH2), 0.89 (t, J=6.9 Hz, 3 H, CH3). EI-MS m/z 276 (M+).3 Results and discussionInitially, we tested the reaction of 2-iodobenzoic acid (1a) with 1-heptyne (2a) under the catalysis of CuI/ trans-4-hydroxy-L-proline by using K2CO3 as base and DMSO as solvent at 90℃(Scheme 1). Desired isocou- marin 3a was isolated in 55% yield. Further attempts indicated that a better yield (70%) could be obtained in the absence of the ligand. In this case other solvents1618WANG LeiLei et al. Sci China Ser B-Chem | Oct. 2009 | vol. 52 | no. 10 | 1616-1621WANG LeiLei et al. Sci China Ser B-Chem | Oct. 2009 | vol. 52 | no. 10 | 1616-1621 1619cyclization products (Table 1, entry 1). The ratio is about 1:0.42 in favor to 6-endo cyclization product. Decre- asing the reaction temperature gave a higher yield while still providing a mixture in a ratio of 1:0.32 (entry 2). Dramatically, when trans -4-hydroxy-L-proline was in- troduced into the reaction system, single isocoumarin 3bwas obtained at different reaction temperatures, although the yields (entries 3―5) decreased to 60%―78%. This reaction process took place even at room temperature(entry 6). In this case low conversion was observed and a mixture of 5-exo and 6-endo cyclization products in aratio of 2.14:1 was obtained. These results demonstrated that substrates, ligands, and reaction temperature havegreat influence on the reaction process.Scheme 1 such as DMF, toluene, EtOH, and dioxane or base (Cs 2CO 3) lead to low yields. It is notable that only 6-endo cyclization product 3a was detected.When we used the optimized reaction conditions to explore the reaction scope, we found that 3-methyl bu-tynyl-2-ol (2b ) gave a mixture of 5-exo and 6-endo Table 1 Effect of reaction conditions on the CuI/ligand-catalyzed cou-pling reaction of 2-halobenzoic acid with terminal alkyne a)When 2-bromobenzoic acid (1b ) was used as a sub-strate, the reaction proceeded smoothly under the cata- lytic system of CuI/trans -4-hydroxy-L-proline, affording single isocoumarin 3b in 79% yield (entry 7). However, in the absence of ligands this reaction gave a mixture of 5-exo and 6-endo cyclization products in low combination yield (entry 8). For additives examined, other amino ac-ids such as L-proline, piperidine-2- carboxylic acid, and picolinic acid gave the similar results (entries 9―11), while β-keto ester E gave a low yield (entry 12). At-tempts to increase or decrease the catalytic loadings failed to improve the results (entries 13 and 14). On thebasis of these studies, we chose to use 20 mol % CuI, 20mol % trans -4-hydroxy-L-proline, K 2CO 3 as base, andDMSO as solvent to run the coupling reaction with2-bromobenzoic acids.Entry X Additive Temp.(℃)Yield (%) b) 1 I ― 90 80(1:0.42) c)2 I ― 70 91(1:0.32) c)3 I A 90 604 I A 70 785 I A 50 626 I A r.t. 24(1:2.14) c)7 Br A 70 798 Br ― 70 13(1:0.35) c)9 Br B 70 7510 Br C 70 8311 Br D 70 7312 Br E 70 23(1:0.21) c)13dBr A 70 65 14e Br A 70 66 The optimized reaction conditions were then tested byvarying aryl bromides and 1-alkynes, and the results were summarized in Table 2. Various alkynes (2b ―2j ) with functional groups were available for this reaction process, leading to the corresponding isocoumarins in good yields (Table 2, entries 1―9). It was notable that dihydroartemidin 3d from 1-butyne could be convertedinto a series of natural isocoumarins via simple trans-formations (entry 3)[32]. In the case of phenylacetyleneas a substrate, the reaction gave a mixture of 3k and 4k(entry 10). This phenomenon is similar to that reportedby Pal [11]. Other 2-bromo benzoic acids with differentsubstituted groups provided isocoumarins in moderate to good yields (entries 11―18). However, 2-bromo-5-nitro benzoic acid and 6-bromo-2,3-dimethoxy benzoic acid tynyl-2-ol (1.5 mmol), CuI (20 mol%), additve (20 mol%), K 2CO 3 (2 mmol),DMSO (1 mL); b) isolated yield; c) the ratio of 3 and 4; d) 10 mol% ofCuI was used; e) 40 mol% of A was used.Table 2 The assembly of isocoumarins via the CuI/ligand-catalyzed cascade processa)Entry 2-Bromo benzoic acidRProduct Yield (%) b)2 3 4 5 6 7 8 9101b511C 4H 8COOEt (2c ) C 4H 9 (2d ) CH 2OH (2e ) CH 2OBn (2f )CH 2NHCOOMe (2g ) CH(OH)C 2H 5 (2h ) CH(OH)C 5H 11 (2i ) CH 2Ph (2j ) Ph (2k ) 3c 3d 3e 3f 3g 3h 3i 3j 3k + 4k82 85 68 66 78 73 68 7154 (1:0.48) c)11 12 131c 2d 2b 2c 3l 3m 3n 85 75 8214 151d2d 2b 3o 3p 73 7216 171e 2d3q69181f2b 2d 3r 3s 7766191g 2b3t 13201h 2d3u23(14 d))Reaction conditions: a) 2-bromo benzoic acid 1 (1.0 mmol), alkyne 2 (1.5 mmol), CuI (20 mol %), trans -4-hydroxy-L-proline (20 mol %), K 2CO 3 (2 mmol), DMSO (1 mL), 70℃, 12h; b) isolated yield; c) the ratio of 3k and 4k ; d) 4u was isolated.gave low yields (entries 19 and 20).4 ConclusionsIn conclusion, we have developed a simple and inexpen- sive method to assemble substituted isocoumarins. 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